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  Subjects -> MEDICAL SCIENCES (Total: 7986 journals)
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MEDICAL SCIENCES (2098 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 3562 Journals sorted alphabetically
16 de Abril     Open Access  
3D Printing in Medicine     Open Access   (Followers: 2)
AADE in Practice     Hybrid Journal   (Followers: 5)
ABCS Health Sciences     Open Access   (Followers: 3)
Abia State University Medical Students' Association Journal     Full-text available via subscription  
ACIMED     Open Access   (Followers: 1)
ACS Medicinal Chemistry Letters     Hybrid Journal   (Followers: 42)
Acta Bio Medica     Full-text available via subscription   (Followers: 2)
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Acta Bioquimica Clinica Latinoamericana     Open Access   (Followers: 1)
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Acta Scientiarum. Health Sciences     Open Access   (Followers: 1)
Acupuncture & Electro-Therapeutics Research     Full-text available via subscription   (Followers: 6)
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Addiction Science & Clinical Practice     Open Access   (Followers: 8)
Addictive Behaviors Reports     Open Access   (Followers: 8)
Adıyaman Üniversitesi Sağlık Bilimleri Dergisi / Health Sciences Journal of Adıyaman University     Open Access  
Adnan Menderes Üniversitesi Sağlık Bilimleri Fakültesi Dergisi     Open Access  
Advanced Biomedical Research     Open Access  
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advanced Science, Engineering and Medicine     Partially Free   (Followers: 8)
Advances in Bioscience and Clinical Medicine     Open Access   (Followers: 6)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26)
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Advances in Parkinson's Disease     Open Access  
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Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
Advances in Regenerative Medicine     Open Access   (Followers: 3)
Advances in Skeletal Muscle Function Assessment     Open Access  
Advances in Therapy     Hybrid Journal   (Followers: 5)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 14)
Advances in Virus Research     Full-text available via subscription   (Followers: 5)
Advances in Wound Care     Hybrid Journal   (Followers: 11)
Aerospace Medicine and Human Performance     Full-text available via subscription   (Followers: 12)
African Health Sciences     Open Access   (Followers: 3)
African Journal of Biomedical Research     Open Access   (Followers: 1)
African Journal of Clinical and Experimental Microbiology     Open Access   (Followers: 2)
African Journal of Laboratory Medicine     Open Access   (Followers: 2)
African Journal of Medical and Health Sciences     Open Access   (Followers: 2)
African Journal of Trauma     Open Access   (Followers: 1)
Afrimedic Journal     Open Access   (Followers: 2)
Aggiornamenti CIO     Hybrid Journal   (Followers: 1)
AIDS Research and Human Retroviruses     Hybrid Journal   (Followers: 9)
AJOB Primary Research     Partially Free   (Followers: 3)
AJSP: Reviews & Reports     Hybrid Journal  
Aktuelle Ernährungsmedizin     Hybrid Journal   (Followers: 4)
Al-Azhar Assiut Medical Journal     Open Access  
Alexandria Journal of Medicine     Open Access   (Followers: 1)
Allgemeine Homöopathische Zeitung     Hybrid Journal   (Followers: 3)
Alpha Omegan     Full-text available via subscription  
ALTEX : Alternatives to Animal Experimentation     Open Access   (Followers: 3)
Althea Medical Journal     Open Access  
American Journal of Biomedical Engineering     Open Access   (Followers: 13)
American Journal of Biomedical Research     Open Access   (Followers: 2)
American Journal of Biomedicine     Full-text available via subscription   (Followers: 7)
American Journal of Chinese Medicine, The     Hybrid Journal   (Followers: 4)
American Journal of Clinical Medicine Research     Open Access   (Followers: 7)
American Journal of Family Therapy     Hybrid Journal   (Followers: 11)
American Journal of Law & Medicine     Full-text available via subscription   (Followers: 11)
American Journal of Lifestyle Medicine     Hybrid Journal   (Followers: 5)
American Journal of Managed Care     Full-text available via subscription   (Followers: 11)
American Journal of Medical Case Reports     Open Access   (Followers: 1)
American Journal of Medical Sciences and Medicine     Open Access   (Followers: 4)
American Journal of Medicine     Hybrid Journal   (Followers: 48)
American Journal of Medicine and Medical Sciences     Open Access   (Followers: 1)
American Journal of Medicine Studies     Open Access   (Followers: 1)
American Journal of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American Journal of the Medical Sciences     Hybrid Journal   (Followers: 12)
American Journal on Addictions     Hybrid Journal   (Followers: 9)
American medical news     Free   (Followers: 3)
American Medical Writers Association Journal     Full-text available via subscription   (Followers: 5)
Amyloid: The Journal of Protein Folding Disorders     Hybrid Journal   (Followers: 5)
Anales de la Facultad de Medicina     Open Access  
Anales de la Facultad de Medicina, Universidad de la República, Uruguay     Open Access  
Anales del Sistema Sanitario de Navarra     Open Access   (Followers: 1)
Analgesia & Resuscitation : Current Research     Hybrid Journal   (Followers: 6)
Anatolian Clinic the Journal of Medical Sciences     Open Access  
Anatomica Medical Journal     Open Access  
Anatomical Science International     Hybrid Journal   (Followers: 3)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1)
Anatomy     Open Access   (Followers: 1)
Anatomy Research International     Open Access   (Followers: 2)
Angewandte Schmerztherapie und Palliativmedizin     Hybrid Journal  
Angiogenesis     Hybrid Journal   (Followers: 3)
Ankara Medical Journal     Open Access   (Followers: 2)
Ankara Üniversitesi Tıp Fakültesi Mecmuası     Open Access  
Annales de Pathologie     Full-text available via subscription  
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Annals of African Medicine     Open Access   (Followers: 2)
Annals of Anatomy - Anatomischer Anzeiger     Hybrid Journal   (Followers: 2)
Annals of Bioanthropology     Open Access   (Followers: 4)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 17)
Annals of Biomedical Sciences     Full-text available via subscription   (Followers: 3)
Annals of Clinical Hypertension     Open Access  
Annals of Clinical Microbiology and Antimicrobials     Open Access   (Followers: 12)
Annals of Family Medicine     Open Access   (Followers: 14)
Annals of Health Research     Open Access  
Annals of Ibadan Postgraduate Medicine     Open Access  
Annals of Medical and Health Sciences Research     Open Access   (Followers: 7)
Annals of Medicine     Hybrid Journal   (Followers: 12)
Annals of Medicine and Surgery     Open Access   (Followers: 7)
Annals of Microbiology     Hybrid Journal   (Followers: 11)
Annals of Nigerian Medicine     Open Access   (Followers: 1)
Annals of Rehabilitation Medicine     Open Access  
Annals of Saudi Medicine     Open Access  
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5)
Annals of The Royal College of Surgeons of England     Full-text available via subscription   (Followers: 3)
Annual Reports in Medicinal Chemistry     Full-text available via subscription   (Followers: 7)
Annual Reports on NMR Spectroscopy     Full-text available via subscription   (Followers: 5)
Annual Review of Medicine     Full-text available via subscription   (Followers: 16)
Anthropological Review     Open Access   (Followers: 23)
Anthropologie et santé     Open Access   (Followers: 5)
Antibiotics     Open Access   (Followers: 9)
Antibodies     Open Access   (Followers: 2)
Antibody Technology Journal     Open Access   (Followers: 1)
Antibody Therapeutics     Open Access  
Anuradhapura Medical Journal     Open Access  
Anwer Khan Modern Medical College Journal     Open Access   (Followers: 2)
Apmis     Hybrid Journal   (Followers: 1)
Apparence(s)     Open Access   (Followers: 1)
Applied Clinical Informatics     Hybrid Journal   (Followers: 3)
Applied Clinical Research, Clinical Trials and Regulatory Affairs     Hybrid Journal  
Applied Medical Informatics     Open Access   (Followers: 12)
Arab Journal of Nephrology and Transplantation     Open Access   (Followers: 1)
Arak Medical University Journal     Open Access  
Archive of Clinical Medicine     Open Access   (Followers: 1)
Archive of Community Health     Open Access   (Followers: 1)
Archives Medical Review Journal / Arşiv Kaynak Tarama Dergisi     Open Access  
Archives of Asthma, Allergy and Immunology     Open Access  
Archives of Medical and Biomedical Research     Open Access   (Followers: 3)
Archives of Medical Laboratory Sciences     Open Access   (Followers: 1)
Archives of Medicine and Health Sciences     Open Access   (Followers: 3)
Archives of Medicine and Surgery     Open Access  
Archives of Trauma Research     Open Access   (Followers: 3)
Archivos de Medicina (Manizales)     Open Access  
ArgoSpine News & Journal     Hybrid Journal  
Arquivos Brasileiros de Oftalmologia     Open Access   (Followers: 1)
Arquivos de Ciências da Saúde     Open Access  
Arquivos de Medicina     Open Access  
Ars Medica : Revista de Ciencias Médicas     Open Access  
ARS Medica Tomitana     Open Access   (Followers: 1)
Art Therapy: Journal of the American Art Therapy Association     Full-text available via subscription   (Followers: 15)
Arterial Hypertension     Open Access   (Followers: 1)
Artificial Intelligence in Medicine     Hybrid Journal   (Followers: 14)
Artificial Organs     Hybrid Journal   (Followers: 1)
ASHA Leader     Open Access  
Asia Pacific Family Medicine     Open Access   (Followers: 1)
Asia Pacific Journal of Clinical Nutrition     Full-text available via subscription   (Followers: 11)
Asia Pacific Journal of Clinical Trials : Nervous System Diseases     Open Access  
Asian Bioethics Review     Full-text available via subscription   (Followers: 3)
Asian Biomedicine     Open Access   (Followers: 2)
Asian Journal of Cell Biology     Open Access   (Followers: 5)
Asian Journal of Health     Open Access   (Followers: 3)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 4)
Asian Journal of Medical and Pharmaceutical Researches     Open Access   (Followers: 1)
Asian Journal of Medical Sciences     Open Access   (Followers: 2)
Asian Journal of Scientific Research     Open Access   (Followers: 3)
Asian Journal of Transfusion Science     Open Access   (Followers: 1)
Asian Medicine     Hybrid Journal   (Followers: 5)
Asian Pacific Journal of Cancer Prevention     Open Access  
ASPIRATOR : Journal of Vector-borne Disease Studies     Open Access  
Astrocyte     Open Access  
Atención Familiar     Open Access  
Atención Primaria     Open Access   (Followers: 1)
Atti della Accademia Peloritana dei Pericolanti - Classe di Scienze Medico-Biologiche     Open Access  
Audiology - Communication Research     Open Access   (Followers: 10)
Auris Nasus Larynx     Full-text available via subscription  
Australian Coeliac     Full-text available via subscription   (Followers: 1)
Australian Family Physician     Full-text available via subscription   (Followers: 3)
Australian Journal of Medical Science     Full-text available via subscription   (Followers: 1)
Autopsy and Case Reports     Open Access  
Avicenna     Open Access   (Followers: 3)
Avicenna Journal of Clinical Medicine     Open Access  
Avicenna Journal of Medicine     Open Access   (Followers: 1)
Bangabandhu Sheikh Mujib Medical University Journal     Open Access   (Followers: 1)

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Journal Cover
Advances in Protein Chemistry and Structural Biology
Journal Prestige (SJR): 0.791
Citation Impact (citeScore): 2
Number of Followers: 20  
 
  Full-text available via subscription Subscription journal
ISSN (Online) 1876-1623
Published by Elsevier Homepage  [3161 journals]
  • From traveler to homebody: Which signaling mechanisms sponge larvae use to
           become adult sponges'
    • Abstract: Publication date: Available online 14 March 2019Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Ilya Borisenko, Olga I. Podgornaya, Alexander V. Ereskovsky Cell-to-cell signaling is responsible for regulation of many developmental processes such as proliferation, cell migration, survival, cell fate specification and axis patterning. In this article we discussed the role of signaling in the metamorphosis of sponges with a focus on epithelial–mesenchymal transition (EMT) accompanying this event. Sponges (Porifera) are an ancient lineage of morphologically simple animals occupying a basal position on the tree of life. The study of these animals is necessary for understanding the origin of multicellularity and the evolution of developmental processes. Development of sponges is quite diverse. It finishes with the metamorphosis of a free-swimming larva into a young settled sponge. The outer surface of sponge larvae consists of a ciliated epithelial sheath, which ensures locomotion, while their internal structure varies from genus to genus. The fate of larval ciliated cells is the most intriguing aspect of metamorphosis. In this review we discuss the fate of larval ciliated cells, the processes going on in cells during metamorphosis at the molecular level and the regulation of this process. The review is based on information about several sponge species with a focus on Halisarca dujardini, Sycon ciliatum and Amphimedon queenslandica. In our model sponge, H. dujardini, ciliated cells leave the larval epithelium during metamorphosis and migrate to the internal cell mass as amoeboid cells to be differentiated into choanocytes of the juvenile sponge. Ciliated cells undergo EMT and internalize within minutes. As EMT involves the disappearance of adherens junctions and as cadherin, the main adherens junction protein, was identified in the transcriptome of several sponges, we suppose that EMT is regulated through cadherin-containing adherens junctions between ciliated cells. We failed to identify the master genes of EMT in the H. dujardini transcriptome, possibly because transcription was absent in the sequenced stages. They may be revealed by a search in the genome. The master genes themselves are controlled by various signaling pathways. Sponges have all the six signaling pathways conserved in Metazoa: Wnt, TGF-beta, Hedgehog, Notch, FGF and NO-dependent pathways. Summarizing the new data about intercellular communication in sponges, we can put forward two main questions regarding metamorphosis: (1) Which of the signaling pathways and in what hierarchical order are involved in metamorphosis' (2) How is the organization of a young sponge related to that of the larva or, in other words, is there a heredity of axes between the larva and the adult sponge'
       
  • Biological functions and clinical implications of interleukin-34 in
           inflammatory diseases
    • Abstract: Publication date: Available online 8 March 2019Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Yun Ge, Man Huang, Xiao-mei Zhu, Yong-ming Yao Interleukin (IL)-34 is a recently discovered cytokine and ligand of the colony-stimulating factor (CSF)-1 receptor. Although CSF-1 and IL-34 share similar biological properties, their expression patterns and downstream signaling pathways are distinct. IL-34 can influence differentiation and has functions in multiple cell types (e.g., dendritic cells, monocytes, macrophages). In the pathological conditions, IL-34 is induced by pro-inflammatory stimuli (e.g., cytokines, pathogen-associated molecular patterns, and infection). Current evidence shows that IL-34 is a critical player in inflammatory response and is involved in the pathogenesis of inflammatory autoimmune dysfunction. Therefore, IL-34 may be a promising clinical biomarker and therapeutic target for treating inflammatory related disorders. In this article, we review the advances in biological functions of IL-34 and our understanding of its role in the development of inflammatory diseases as well as therapeutic applications.
       
  • Dopamine signaling in the striatum
    • Abstract: Publication date: Available online 22 February 2019Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Emmanuel Valjent, Anne Biever, Giuseppe Gangarossa, Emma Puighermanal The striatum integrates dopamine-mediated reward signals to generate appropriate behavior in response to glutamate-mediated sensory cues. Such associative learning relies on enduring neural plasticity in striatal GABAergic spiny projection neurons which, when altered, can lead to the development of a wide variety of pathological states. Considerable progress has been made in our understanding of the intracellular signaling mechanisms in dopamine-related behaviors and pathologies. Through the prism of the regulation of histone H3 and ribosomal protein S6 phosphorylation, we review how dopamine-mediated signaling events regulate gene transcription and mRNA translation. Particularly, we focus on the intracellular cascades controlling these phosphorylations downstream of the modulation of dopamine receptors by psychostimulants, antipsychotics and l-DOPA. Finally, we highlight the importance to precisely determine in which neuronal populations these signaling events occur in order to understand how they participate in remodeling neural circuits and altering dopamine-related behaviors.
       
  • TFIIH: A multi-subunit complex at the cross-roads of transcription and DNA
           repair
    • Abstract: Publication date: Available online 10 February 2019Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Olga Kolesnikova, Laura Radu, Arnaud Poterszman Transcription factor IIH (TFIIH) is a multiprotein complex involved in both eukaryotic transcription and DNA repair, revealing a tight connection between these two processes. Composed of 10 subunits, it can be resolved into a 7-subunits core complex with the XPB translocase and the XPD helicase, and the 3-subunits kinase complex CAK, which also exists as a free complex with a distinct function. Initially identified as basal transcription factor, TFIIH also participates in transcription regulation and plays a key role in nucleotide excision repair (NER) for opening DNA at damaged sites, lesion verification and recruitment of additional repair factors. Our understanding of TFIIH function in eukaryotic cells has greatly benefited from studies of the genetic rare diseases xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD), that are not only characterized by cancer and aging predispositions but also by neurological and developmental defects. Although much remains unknown about TFIIH function, significant progresses have been done regarding the structure of the complex, the functions of its catalytic subunits and the multiple roles of the regulatory core-TFIIH subunits. This review provides a non-exhaustive survey of key discoveries on the structure and function of this pivotal factor, which can be considered as a promising target for therapeutic strategies.
       
  • Estrogen receptor signaling mechanisms
    • Abstract: Publication date: Available online 4 February 2019Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Nathalie Fuentes, Patricia Silveyra The primary female sex hormones, estrogens, are responsible for the control of functions of the female reproductive system, as well as the development of secondary sexual characteristics that appear during puberty and sexual maturity. Estrogens exert their actions by binding to specific receptors, the estrogen receptors (ERs), which in turn activate transcriptional processes and/or signaling events that result in the control of gene expression. These actions can be mediated by direct binding of estrogen receptor complexes to specific sequences in gene promoters (genomic effects), or by mechanisms that do not involve direct binding to DNA (non-genomic effects). Whether acting via direct nuclear effects, indirect non-nuclear actions, or a combination of both, the effects of estrogens on gene expression are controlled by highly regulated complex mechanisms. In this chapter, we summarize the knowledge gained in the past 60 years since the discovery of the estrogen receptors on the mechanisms governing estrogen-mediated gene expression. We provide an overview of estrogen biosynthesis, and we describe the main mechanisms by which the female sex hormone controls gene transcription in different tissues and cell types. Specifically, we address the molecular events governing regulation of gene expression via the nuclear estrogen receptors (ERα, and ERβ) and the membrane estrogen receptor (GPER1). We also describe mechanisms of cross-talk between signaling cascades activated by both nuclear and membrane estrogen receptors. Finally, we discuss natural compounds that are able to target specific estrogen receptors and their implications for human health and medical therapeutics.
       
  • Molecular signaling in bone cells: Regulation of cell differentiation and
           survival
    • Abstract: Publication date: Available online 4 February 2019Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Lilian I. Plotkin, Angela Bruzzaniti The achievement of proper bone mass and architecture, and their maintenance throughout life requires the concerted actions of osteoblasts, the bone forming cells, and osteoclasts, the bone resorbing cells. The differentiation and activity of osteoblasts and osteoclasts are regulated by molecules produced by matrix-embedded osteocytes, as well as by cross talk between osteoblasts and osteoclasts through secreted factors. In addition, it is likely that direct contact between osteoblast and osteoclast precursors, and the contact of these cells with osteocytes and cells in the bone marrow, also modulates bone cell differentiation and function. With the advancement of molecular and genetic tools, our comprehension of the intracellular signals activated in bone cells has evolved significantly, from early suggestions that osteoblasts and osteoclasts have common precursors and that osteocytes are inert cells in the bone matrix, to the very sophisticated understanding of a network of receptors, ligands, intracellular kinases/phosphatases, transcription factors, and cell-specific genes that are known today. These advances have allowed the design and FDA-approval of new therapies to preserve and increase bone mass and strength in a wide variety of pathological conditions, improving bone health from early childhood to the elderly. We have summarized here the current knowledge on selected intracellular signal pathways activated in osteoblasts, osteocytes, and osteoclasts.
       
  • Intracellular signaling of the AMP-activated protein kinase
    • Abstract: Publication date: Available online 14 January 2019Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Miribane Dërmaku-Sopjani, Mentor Sopjani AMP-activated protein kinase (AMPK) is an essential cellular energy sensor that senses the cellular energy status and maintains cellular energy balance. The AMPK coordinates cellular and whole-body energy homeostasis through stimulating catabolic ATP-producing and suppressing anabolic ATP-consuming intracellular signaling pathways. AMPK induces autophagy and inhibits cell growth in response to starvation, a process that involves regulating certain intracellular signaling molecules. Recent advances demonstrated the AMPK to exert tumor suppressor activity realized through various signaling molecules by stimulating different cellular processes such as apoptosis, autophagy and cell growth and proliferation. AMPK can also be used to protect against metabolic syndrome. AMPK has previously been reported to be either directly or indirectly involved in the regulation of many different cellular transport proteins of high importance for cellular physiology and pathophysiology. Thus, AMPK provides a necessary link between cellular energy metabolism and cellular transport activities. A better understanding of the AMPK role in intracellular signaling under physiological and pathological conditions may represent a potential strategy for developing therapies for treating many different human diseases and disorders, in which AMPK plays a key role.
       
  • Elucidating the role of interacting residues of the MSH2-MSH6 complex in
           DNA repair mechanism: A computational approach
    • Abstract: Publication date: Available online 7 January 2019Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): D. Thirumal Kumar, B. Susmita, E. Judith, J. Priyadharshini Christy, C. George Priya Doss, Hatem Zayed The DNA repair system is crucial to repair the error resulting in DNA replication. MSH2-MSH6 protein complex plays a significant role in maintaining the mismatch repair mechanism. Mutations in the interface between the two proteins compromise their function in the repair process. The present study aims to understand the impact of missense mutations in the interacting sites of the MSH2-MSH6 protein complex. MSH6 is unstable due to the disordered N-terminal domain. This is stabilized by the MSH2 hetero-dimerization. We used pathogenicity and stability predictors to identify the missense mutations that could be more pathogenic with the destabilizing property. The mutations W764C of MSH2, and L1201F and G1316E of MSH6 were predicted to be highly deleterious and destabilizing by all the in silico predictors. The dynamic motion of the native and mutant (W764C) MSH2-MSH6 protein complexes was further investigated using Molecular Dynamics Simulations of the GROMACS package. The Root Mean Square Deviation (RMSD), Radius of Gyration (Rg), and change in a number of intramolecular hydrogen bonds (H-bonds) were analyzed using the embedded packages of GROMACS. From the simulation studies, we observed higher deviation, lower protein compactness, and a decrease in the number of intramolecular hydrogen bonds in the mutant W764C MSH2-MSH6 protein complex. The observed results from the computational methods suggest the involvement of higher structural impact on the MSH2-MSH6 protein complex upon W764C mutation could affect the DNA repair mechanism.
       
  • A computational model to predict the structural and functional
           consequences of missense mutations in O6-methylguanine DNA
           methyltransferase
    • Abstract: Publication date: Available online 7 January 2019Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): D. Thirumal Kumar, Enid Mendonca, J. Priyadharshini Christy, C. George Priya Doss, Hatem Zayed DNA repair mechanism is a process through which the cell repairs its damaged DNA. Although there are several mechanisms involved in the DNA repair mechanisms, the direct reversal method is the simplest and does not require a reference template, in which the guanine bases are often methylated, and the methyl guanine methyl transferase protein (MGMT) reverses them. The mutations occurring in the MGMT protein might result in dysfunction of such DNA repair mechanism. In this study, we attempted to evaluate the impact of six missense mutations (Y114E, Y114A, R128G, R128A, R128K, and C145A) at three active-site positions (Y114, C145, and R128) as this might hinder the DNA binding to the protein. These six mutations were subjected to pathogenicity, stability, and conservation analysis using online servers such as PredictSNP, iStable, and ConSurf, respectively. From the predictions, all the six mutations were almost predicted to be significant. Considering true positives, true negatives, false positives, and false negatives, three mutations (Y114E, R128G, and C145A) showed “loss of DNA repair activity,” and were analyzed further using molecular dynamics simulations (MDS) using GROMACS for 50 ns. MDS run showed that the C145A mutant demonstrated higher structural deviation, decreased compactness, and the binding patterns. The Y114E mutant showed almost a null effect from the structural analysis. Finally, the R128G mutant showed structural variations in between the C145A and Y114E mutations of MGMT protein. We believe that the observed findings in this computational approach might further pave a way of providing better treatment measures by understanding the DNA repair mechanisms.
       
  • Aquaporin water channels: New perspectives on the potential role in
           inflammation
    • Abstract: Publication date: Available online 5 January 2019Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Margherita Sisto, Domenico Ribatti, Sabrina Lisi Aquaporins (AQPs) are a family of membrane water channel proteins that osmotically modulate water fluid homeostasis in several tissues; some of them also transport small solutes such as glycerol. At the cellular level, the AQPs regulate not only cell migration and transepithelial fluid transport across membranes, but also common events that are crucial for the inflammatory response. Emerging data reveal a new function of AQPs in the inflammatory process, as demonstrated by their dysregulation in a wide range of inflammatory diseases including edematous states, cancer, obesity, wound healing and several autoimmune diseases. This chapter summarizes the discoveries made so far about the structure and functions of the AQPs and provides updated information on the underlying mechanisms of AQPs in several human inflammatory diseases. The discovery of new functions for AQPs opens new vistas offering promise for the discovery of mechanisms and therapeutic opportunities in inflammatory disorders.
       
  • Mechanistic link between DNA damage sensing, repairing and signaling
           factors and immune signaling
    • Abstract: Publication date: Available online 3 January 2019Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Shibani Mukherjee, Salim Abdisalaam, Souparno Bhattacharya, Kalayarasan Srinivasan, Debapriya Sinha, Aroumougame Asaithamby Previously, DNA damage sensing, repairing and signaling machineries were thought to mainly suppress genomic instability in response to genotoxic stress. Emerging evidence indicates a crosstalk between DNA repair machinery and the immune system. In this chapter, we attempt to decipher the molecular choreography of how factors, including ATM, BRCA1, DNA-PK, FANCA/D2, MRE11, MUS81, NBS1, RAD51 and TREX1, of multiple DNA metabolic processes are directly or indirectly involved in suppressing cytosolic DNA sensing pathway-mediated immune signaling. We provide systematic details showing how different DDR factors’ roles in modulating immune signaling are not direct, but are rather a consequence of their inherent ability to sense, repair and signal in response to DNA damage. Unexpectedly, most DDR factors negatively impact the immune system; that is, the immune system shows defective signaling if there are defects in DNA repair pathways. Thus, in addition to their known DNA repair and replication functions, DDR factors help prevent erroneous activation of immune signaling. A more precise understanding of the mechanisms by which different DDR factors function in immune signaling can be exploited to redirect the immune system for both preventing and treating autoimmunity, cellular senescence and cancer in humans.
       
  • Recent advances in computational studies of GPCR-G protein interactions
    • Abstract: Publication date: Available online 3 January 2019Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Jinan Wang, Yinglong Miao Protein-protein interactions are key in cellular signaling. G protein-coupled receptors (GPCRs), the largest superfamily of human membrane proteins, are able to transduce extracellular signals (e.g., hormones and neurotransmitters) to intracellular proteins, in particular the G proteins. Since GPCRs serve as primary targets of ~ 1/3 of currently marketed drugs, it is important to understand mechanisms of GPCR signaling in order to design selective and potent drug molecules. This chapter focuses on recent advances in computational studies of the GPCR-G protein interactions using bioinformatics, protein-protein docking and molecular dynamics simulation approaches.
       
  • Replication stress: Driver and therapeutic target in genomically instable
           cancers
    • Abstract: Publication date: Available online 28 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Pepijn M. Schoonen, Sergi Guerrero Llobet, Marcel A.T.M. van Vugt Genomically instable cancers are characterized by progressive loss and gain of chromosomal fragments, and the acquisition of complex genomic rearrangements. Such cancers, including triple-negative breast cancers and high-grade serous ovarian cancers, typically show aggressive behavior and lack actionable driver oncogenes. Increasingly, oncogene-induced replication stress or defective replication fork maintenance is considered an important driver of genomic instability. Paradoxically, while replication stress causes chromosomal instability and thereby promotes cancer development, it intrinsically poses a threat to cellular viability. Apparently, tumor cells harboring high levels of replication stress have evolved ways to cope with replication stress. As a consequence, therapeutic targeting of such compensatory mechanisms is likely to preferentially target cancers with high levels of replication stress and may prove useful in potentiating chemotherapeutic approaches that exert their effects by interfering with DNA replication. Here, we discuss how replication stress drives chromosomal instability, and the cell cycle-regulated mechanisms that cancer cells employ to deal with replication stress. Importantly, we discuss how mechanisms involving DNA structure-specific resolvases, cell cycle checkpoint kinases and mitotic processing of replication intermediates offer possibilities in developing treatments for difficult-to-treat genomically instable cancers.
       
  • Relationship between mitofusin 2 and cancer
    • Abstract: Publication date: Available online 27 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): A. Allegra, V. Innao, A.G. Allegra, C. Musolino Mitochondria are dynamic organelles whose actions are fundamental for cell viability. Within the cell, the mitochondrial system is incessantly modified via the balance between fusion and fission processes. Among other proteins, mitofusin 2 is a central protagonist in all these mitochondrial events (fusion, trafficking, contacts with other organelles), the balance of which causes the correct mitochondrial action, shape, and distribution within the cell. Here we examine the structural and functional characteristics of mitofusin 2, underlining its essential role in numerous intracellular pathways, as well as in the pathogenesis of cancer.
       
  • Activating mutations of the gp130/JAK/STAT pathway in human diseases
    • Abstract: Publication date: Available online 27 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Juliane Lokau, Christoph Garbers Cytokines of the interleukin-6 (IL-6) family are involved in numerous physiological and pathophysiological processes. Dysregulated and increased activities of its members can be found in practically all human inflammatory diseases including cancer. All cytokines activate several intracellular signaling cascades, including the Jak/STAT, MAPK, PI3K, and Src/YAP signaling pathways. Additionally, several mutations in proteins involved in these signaling cascades have been identified in human patients, which render these proteins constitutively active and result in a hyperactivation of the signaling pathway. Interestingly, some of these mutations are associated with or even causative for distinct human diseases, making them interesting targets for therapy. This chapter describes the basic biology of the gp130/Jak/STAT pathway, summarizes what is known about the molecular mechanisms of the activating mutations, and gives an outlook how this knowledge can be exploited for targeted therapy in human diseases.
       
  • DNA repair by photolyases
    • Abstract: Publication date: Available online 20 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Ibrahim Halil Kavakli, Nuri Ozturk, Seref Gul Photolyases belong to the cryptochrome/photolyase protein family (CPF) which perform different functions such as DNA repair, circadian photoreceptor, and transcriptional regulation. Photolyase is a flavoprotein that repairs UV-induced DNA damages of cyclobutane pyrimidine dimer (CPD) and pyrimidine-pyrimidone (6-4) photoproducts using blue-light as an energy source. This enzyme has two chromophores: flavin adenine dinucleotide (FAD) as a cofactor and a photoantenna such as methenyltetrahydrofolate (MTHF). The FAD is essential for catalysis of the DNA repair. The second chromophore absorbs photons from the blue light spectrum and transfers energy to FAD to increase the repair efficiency of the enzyme. Phylogenetic analysis in which amino acid sequences of several hundreds of CPF members are used suggests that they form more classes than we have considered so far. In this chapter, we discussed structure-functions and reaction mechanisms of different classes of photolyases.
       
  • Intracellular protein complexes involved in synapse assembly in
           presynaptic neurons
    • Abstract: Publication date: Available online 20 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Kyung Ah Han, Ji Won Um, Jaewon Ko The presynaptic active zone, composed of evolutionarily conserved protein complexes, is a specialized area that serves to orchestrate precise and efficient neurotransmitter release by organizing various presynaptic proteins involved in mediating docking and priming of synaptic vesicles, recruiting voltage-gated calcium channels, and modulating presynaptic nerve terminals with aligned postsynaptic structures. Among membrane proteins localized to active zone, presynaptic neurexins and LAR-RPTPs (leukocyte common antigen-related receptor tyrosine phosphatase) have emerged as hubs that orchestrate both shared and distinct extracellular synaptic adhesion pathways. In this chapter, we discuss intracellular signaling cascades involved in recruiting various intracellular proteins at both excitatory and inhibitory synaptic sites. In particular, we highlight recent studies on key active zone proteins that physically and functionally link these cascades with neurexins and LAR-RPTPs in both vertebrate and invertebrate model systems. These studies allow us to build a general, universal view of how presynaptic active zones operate together with postsynaptic structures in neural circuits.
       
  • Chromatin control in double strand break repair
    • Abstract: Publication date: Available online 20 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Anastas Gospodinov, Iva Ugrinova DNA double strand breaks (DSB) are the most deleterious type of damage inflicted on DNA by various environmental factors and as consequences of normal cellular metabolism. The multistep nature of DSB repair and the need to assemble large protein complexes at repair sites necessitate multiple chromatin changes there. This review focuses on the key findings of how chromatin regulators exert temporal and spatial control on DSB repair. These mechanisms coordinate repair with cell cycle progression, lead to DSB repair pathway choice, provide accessibility of repair machinery to damaged sites and move the lesions to nuclear environments permissive for repair.
       
  • The roles of cytosolic quality control proteins, SGTA and the BAG6
           complex, in disease
    • Abstract: Publication date: Available online 18 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Rashi Benarroch, Jennifer M. Austin, Fahmeda Ahmed, Rivka L. Isaacson SGTA is a co-chaperone that, in collaboration with the complex of BAG6/UBL4A/TRC35, facilitates the biogenesis and quality control of hydrophobic proteins, protecting them from the aqueous cytosolic environment. This work includes targeting tail-anchored proteins to their resident membranes, sorting of membrane and secretory proteins that mislocalize to the cytoplasm and endoplasmic reticulum-associated degradation of misfolded proteins. Since these functions are all vital for the cell's continued proteostasis, their disruption poses a threat to the cell, with a particular risk of protein aggregation, a phenomenon that underpins many diseases. Although the specific disease implications of machinery involved in quality control of hydrophobic substrates are poorly understood, here we summarize much of the available information on this topic.
       
  • Computational and modeling approaches to understand the impact of the
           Fabry's disease causing mutation (D92Y) on the interaction with
           pharmacological chaperone 1-deoxygalactonojirimycin (DGJ)
    • Abstract: Publication date: Available online 18 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): D. Thirumal Kumar, E. Judith, J. Priya dharshini Christy, R. Siva, Iftikhar Aslam Tayubi, Chiranjib Chakraborty, C. George Priya Doss, Hatem Zayed Fabry's disease (FD) is the second most commonly occurring lysosomal storage disorders (LSDs). The mutations in GLA protein were widely found to be causative for the Fabry's disease. These mutations result in alternate splicing methods that affect the stability and function of the protein. The mutations near the active site of the protein results in protein misfolding. In this study, we have retrieved the missense mutation data from the three public databases (NCBI, UniProt, and HGMD). We used multiple in silico tools to predict the pathogenicity and stability of these mutations. Mutations in the active sites (D92Y, C142Y, D170V, and D266N) of the protein were screened for the phenotyping analysis using SNPeffect 4.0. Mutant D92Y was predicted to increase the amyloid propensity as well as severely reduce the protein stability and the remaining mutations showed no significant results by SNPeffect 4.0. Protein dynamics simulations (PDS) were performed to understand the behavior of the proteins due to the mutations. The simulation results showed that the D92Y mutant was more severe (higher deviation, loss of intramolecular hydrogen bonds, and lower compactness) than the other protein mutants (C142Y, D170V, and D266N). Further, the action of pharmacological chaperone 1-deoxygalactonojirimycin (DGJ) over the severe mutation was studied using the molecular docking analysis. Chaperone DGJ, an iminosugar plays a convincing role in repairing the misfolded protein and helps the protein to achieve its normal function. From the molecular docking analysis, we observed that both the native protein and protein with D92Y mutation followed similar interaction patterns. Further, the docked complexes (native-DGJ and mutant-DGJ) were subjected to PDS analysis. From the simulation analysis, we observed that DGJ had shown the better effect on the protein with the D92Y mutation. This elucidates that DGJ can still be used as a promising chaperone to treat the FD caused by mutations of GLA protein.
       
  • When safeguarding goes wrong: Impact of oxidative stress on protein
           homeostasis in health and neurodegenerative disorders
    • Abstract: Publication date: Available online 18 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Ravit Mesika, Dana Reichmann Cellular redox status is an established player in many different cellular functions. The buildup of oxidants within the cell is tightly regulated to maintain a balance between the positive and negative outcomes of cellular oxidants. Proteins are highly sensitive to oxidation, since modification can cause widespread unfolding and the formation of toxic aggregates. In response, cells have developed highly regulated systems that contribute to the maintenance of both the global redox status and protein homeostasis at large. Changes to these systems have been found to correlate with aging and age-related disorders, such as neurodegenerative pathologies. This raises intriguing questions as to the source of the imbalance in the redox and protein homeostasis systems, their interconnectivity, and their role in disease progression.Here we focus on the crosstalk between the redox and protein homeostasis systems in neurodegenerative diseases, specifically in Alzheimer's, Parkinson's, and ALS. We elaborate on some of the main players of the stress response systems, including the master regulators of oxidative stress and the heat shock response, Nrf2 and Hsf1, which are essential features of protein folding, and mediators of protein turnover. We illustrate the elegant mechanisms used by these components to provide an immediate response, including protein plasticity controlled by redox-sensing cysteines and the recruitment of naive proteins to the redox homeostasis array that act as chaperons in an ATP-independent manner.
       
  • Claspin: From replication stress and DNA damage responses to cancer
           therapy
    • Abstract: Publication date: Available online 5 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Diana Azenha, Maria Celeste Lopes, Teresa C. Martins Cancer is still one of the major causes of death worldwide. Radiation therapy and chemotherapy remain the main treatment modalities in cancer. These therapies exert their effect mainly through interference with DNA replication and induction of DNA damage. It is believed that one way of improving the efficacy of cancer treatment will be to inhibit the replication stress and DNA damage responses and promote mitotic catastrophe of cancer cells. So far, the majority of the efforts have focused central players of checkpoint responses, such as ATR and CHK1, and DNA damage repair, such as PARPs. Being a key player in the replication stress response, checkpoint activation, and the DNA damage response, Claspin constitutes an attractive therapeutic target in cancer, namely for radio- and chemo-sensitization. In this review, we will go through Claspin functions in the replication stress and DNA damage responses and will discuss how Claspin can be targeted in cancer treatment, as well as the effects of Claspin inhibition.
       
  • Controlling the balance between chromosome break repair pathways
    • Abstract: Publication date: Available online 5 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Sonia Jimeno, Fernando Mejías-Navarro, Rosario Prados-Carvajal, Pablo Huertas Broken chromosomes are among the most complex and more difficult to repair DNA lesions. The loss of the continuity of the DNA molecule presents a challenge to the cells, thus the repair of DNA double strand breaks might lead to genomic alterations. Indeed, to minimize this threat to genomic integrity, different DNA repair pathways can act on a broken chromosome. The balance between them is tightly controlled, and it heavily depends on global and local cellular cues. In this chapter, we review our current understanding on the repair of DNA double strand breaks and focus in the regulation of the balance between alternative pathways. Most of this modulation takes place at the level of DNA end resection. Here, we focus mostly on the local signals that control the repair pathway choice, as the global cues have been extensively reviewed recently. We described epigenetic marks that either facilitate or inhibit DNA resection and homologous recombination, from histone marks and chromatin remodelers to non-coding RNA and RNA-related factors.
       
  • cAMP-mediated regulation of melanocyte genomic instability: A
           melanoma-preventive strategy
    • Abstract: Publication date: Available online 5 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Nathaniel C. Holcomb, Robert-Marlo Bautista, Stuart G. Jarrett, Katharine M. Carter, Madeline Krentz Gober, John A. D’Orazio Malignant melanoma of the skin is the leading cause of death from skin cancer and ranks fifth in cancer incidence among all cancers in the United States. While melanoma mortality has remained steady for the past several decades, melanoma incidence has been increasing, particularly among fair-skinned individuals. According to the American Cancer Society, nearly 10,000 people in the United States will die from melanoma this year. Individuals with dark skin complexion are protected damage generated by UV-light due to the high content of UV-blocking melanin pigment in their epidermis as well as better capacity for melanocytes to cope with UV damage. There is now ample evidence that suggests that the melanocortin 1 receptor (MC1R) is a major melanoma risk factor. Inherited loss-of-function mutations in MC1R are common in melanoma-prone persons, correlating with a less melanized skin complexion and poorer recovery from mutagenic photodamage. We and others are interested in the MC1R signaling pathway in melanocytes, its mechanisms of enhancing genomic stability and pharmacologic opportunities to reduce melanoma risk based on those insights. In this chapter, we review melanoma risk factors, the MC1R signaling pathway, and the relationship between MC1R signaling and DNA repair.
       
  • Targeting DNA repair in precision medicine
    • Abstract: Publication date: Available online 5 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Reena Beggs, Eddy S. Yang Precision medicine is an emerging treatment paradigm that aims to find the right therapy at the right time based on an individual's unique genetic background, environment, and lifestyle. One area of precision medicine that has had success is targeting DNA repair in cancer. DNA is exposed to constant stress and there are repair mechanisms in place to maintain genetic integrity. These repair mechanisms can be targeted as a treatment strategy. In this chapter, we will focus on current efforts to target DNA repair pathways as part of precision oncology-based treatments.
       
  • Functional principles and regulation of molecular chaperones
    • Abstract: Publication date: Available online 1 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Vinay Dahiya, Johannes Buchner To be able to perform their biological function, a protein needs to be correctly folded into its three dimensional structure. The protein folding process is spontaneous and does not require the input of energy. However, in the crowded cellular environment where there is high risk of inter-molecular interactions that may lead to protein molecules sticking to each other, hence forming aggregates, protein folding is assisted. Cells have evolved robust machinery called molecular chaperones to deal with the protein folding problem and to maintain proteins in their functional state. Molecular chaperones promote efficient folding of newly synthesized proteins, prevent their aggregation and ensure protein homeostasis in cells. There are different classes of molecular chaperones functioning in a complex interplay. In this review, we discuss the principal characteristics of different classes of molecular chaperones, their structure-function relationships, their mode of regulation and their involvement in human disorders.
       
  • A comparative computational approach toward pharmacological chaperones
           (NN-DNJ and ambroxol) on N370S and L444P mutations causing Gaucher's
           disease
    • Abstract: Publication date: Available online 1 December 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): D. Thirumal Kumar, Sharada Iyer, J. Priyadharshini Christy, R. Siva, Iftikhar Aslam Tayubi, C. George Priya Doss, Hatem Zayed Gaucher's disease (GD) is the most commonly known lysosomal disorder that occurs due to mutations in the β-glucocerebrosidase (GBA) protein. Our previous findings (Thirumal Kumar, Eldous, Mahgoub, George Priya Doss, Zayed, 2018) and other reports concluded that the mutations N370S and L444P are the most significant mutations that could cause disruptions in protein stability and structure. These disruptions lead to protein misfolding and result in a diseased condition. Enzyme Replacement Therapy (ERT) and Pharmacological chaperone therapy (PCT) are currently used to treat GD caused by mutations in the GBA protein. The extreme disparity in cost between ERT and chaperone therapy, shifted the attention toward chaperone therapy. The most common chaperones in the market and trial phases to treat GD are Isofagomine, Miglustat, Eliglustat, NN-DNJ, and Ambroxol. In the era of personalized medicine, it is often necessary to understand the drug likeliness of each chaperone. In this context, the present study utilized molecular docking analysis to understand the interaction behavior of the chaperone toward the native and the two mutants N370S and L444P. The molecular dynamics simulation analyses performed on chaperones (NN-DNJ and Ambroxol) interaction showed that the chaperone NN-DNJ possesses better affinity toward the protein with N370S mutation whereas chaperone Ambroxol showed better activity against both the significant mutations (N370S and L444P). This study is expected to serve as a platform for drug repurposing.
       
  • Protein stability and degradation in health and disease
    • Abstract: Publication date: Available online 28 November 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Lene Clausen, Amanda B. Abildgaard, Sarah K. Gersing, Amelie Stein, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen The cellular proteome performs highly varied functions to sustain life. Since most of these functions require proteins to fold properly, they can be impaired by mutations that affect protein structure, leading to diseases such as Alzheimer's disease, cystic fibrosis, and Lynch syndrome. The cell has evolved an intricate protein quality control (PQC) system that includes degradation pathways and a multitude of molecular chaperones and co-chaperones, all working together to catalyze the refolding or removal of aberrant proteins. Thus, the PQC system limits the harmful consequences of dysfunctional proteins, including those arising from disease-causing mutations. This complex system is still not fully understood. In particular the structural and sequence motifs that, when exposed, trigger degradation of misfolded proteins are currently under investigation. Moreover, several attempts are being made to activate or inhibit parts of the PQC system as a treatment for diseases. Here, we briefly review the present knowledge on the PQC system and list current strategies that are employed to exploit the system in disease treatment.
       
  • Inflammatory response and its relation to sphingolipid metabolism
           proteins: Chaperones as potential indirect anti-inflammatory agents
    • Abstract: Publication date: Available online 28 November 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Z. Begum Yagci, Elif Esvap, Hatice Asuman Ozkara, Kutlu O. Ulgen, Elif Ozkirimli Lysosome is the organelle responsible for breaking down macromolecules to maintain homeostasis and to fight infection. The disruption of normal lysosomal function due to mutations in the sphingolipid metabolism proteins leads to a class of lysosomal storage diseases (LSDs). Defective autophagy and activation of inflammation are observed in most LSDs. The crosstalk between these key metabolic pathways suggests that therapeutic approaches used in the treatment of LSDs may provide anti-inflammatory therapies against chronic inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease. Here, we review the role of sphingolipids in the inflammatory response and build a protein-protein interaction network for proteins related with sphingolipid metabolism and inflammation to identify key interaction partners for the crosstalk between sphingolipids and inflammation. In addition, we present an overview of LSDs in relation with sphingolipids and inflammation, and review the pharmacological chaperones identified for these diseases.
       
  • Structural and functional insights on the roles of molecular chaperones in
           the mistargeting and aggregation phenotypes associated with primary
           hyperoxaluria type I
    • Abstract: Publication date: Available online 28 November 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): José Ángel Fernández-Higuero, Isabel Betancor-Fernández, Noel Mesa-Torres, Arturo Muga, Eduardo Salido, Angel L. Pey To carry out their biological function in cells, proteins must be folded and targeted to the appropriate subcellular location. These processes are controlled by a vast collection of interacting proteins collectively known as the protein homeostasis network, in which molecular chaperones play a prominent role. Protein homeostasis can be impaired by inherited mutations leading to genetic diseases. In this chapter, we focus on a particular disease, primary hyperoxaluria type 1 (PH1), in which disease-associated mutations exacerbate protein aggregation in the cell and mistarget the peroxisomal alanine:glyoxylate aminotransferase (AGT) protein to mitochondria, in part due to native state destabilization and enhanced interaction with Hsp60, 70 and 90 chaperone systems. After a general introduction of molecular chaperones and PH1, we review our current knowledge on the structural and energetic features of PH1-causing mutants that lead to these particular pathogenic mechanisms. From this perspective, and in the context of the key role of molecular chaperones in PH1 pathogenesis, we present and discuss current and future perspectives for pharmacological treatments for this disease.
       
  • Chaperones and retinal disorders
    • Abstract: Publication date: Available online 28 November 2018Source: Advances in Protein Chemistry and Structural BiologyAuthor(s): Maxim Sokolov, Ravi P. Yadav, Celine Brooks, Nikolai O. Artemyev Defects in protein folding and trafficking are a common cause of photoreceptor degeneration, causing blindness. Photoreceptor cells present an unusual challenge to the protein folding and transport machinery due to the high rate of protein synthesis, trafficking and the renewal of the outer segment, a primary cilium that has been modified into a specialized light-sensing compartment. Phototransduction components, such as rhodopsin and cGMP-phosphodiesterase, and multimeric ciliary transport complexes, such as the BBSome, are hotspots for mutations that disrupt proteostasis and lead to the death of photoreceptors. In this chapter, we review recent studies that advance our understanding of the chaperone and transport machinery of phototransduction proteins.
       
 
 
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