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Protein disorder

Florent Xavier Smit, Jurriaan A Luiken, Peter G Bolhuis
We performed replica exchange molecular dynamics and forward flux sampling simulations of hexapeptide VQIINK and VQIVYK systems, also known as, respectively, fragments PHF6* and PHF6 from tau protein. Part of the microtubule binding region, these fragments are known to be aggregation prone, and at least one of them is a prerequisite for fibril formation of the tau protein. Using a coarse-grained force field, we establish the phase behavior of both fragments, and investigate the nucleation kinetics for the conversion into a β-sheet fibril...
October 24, 2016: Journal of Physical Chemistry. B
Monika B Dolinska, Nicole Kus, Katie Farney, Paul T Wingfield, Brian P Brooks, Yuri V Sergeev
: Oculocutaneous albinism Type 1 (OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. Two subtypes of OCA1 have been described: severe OCA1A with complete absence of tyrosinase activity and less severe OCA1B with residual tyrosinase activity. Here, we characterize the recombinant human tyrosinase intra-melanosomal domain and mutant variants, which mimic genetic changes in both subtypes of OCA1 patients. Proteins were prepared using site-directed mutagenesis, expressed in insect larvae, purified by chromatography, and characterized by enzymatic activities- tryptophan fluorescence, and Gibbs free energy changes...
October 24, 2016: Pigment Cell & Melanoma Research
Gráinne S Gorman, Patrick F Chinnery, Salvatore DiMauro, Michio Hirano, Yasutoshi Koga, Robert McFarland, Anu Suomalainen, David R Thorburn, Massimo Zeviani, Douglass M Turnbull
Mitochondrial diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode structural mitochondrial proteins or proteins involved in mitochondrial function. Mitochondrial diseases are the most common group of inherited metabolic disorders and are among the most common forms of inherited neurological disorders. One of the challenges of mitochondrial diseases is the marked clinical variation seen in patients, which can delay diagnosis...
October 20, 2016: Nature Reviews. Disease Primers
Siliang Xu, Ping Duan, Jinping Li, Tristan Senkowski, Fengbiao Guo, Haibin Chen, Alberto Romero, Yugui Cui, Jiayin Liu, Shi-Wen Jiang
SET (SE Translocation) protein carries out multiple functions including those for protein phosphatase 2A (PP2A) inhibition, histone modification, DNA repair, and gene regulation. SET overexpression has been detected in brain neurons of patients suffering Alzheimer's disease, follicle theca cells of Polycystic Ovary Syndrome (PCOS) patients, and ovarian cancer cells, indicating that SET may play a pathological role for these disorders. SET transcript 2, produced by a specific promoter, represents a major transcript variant in different cell types...
October 20, 2016: International Journal of Molecular Sciences
Henrieta Škovierová, Eva Vidomanová, Silvia Mahmood, Janka Sopková, Anna Drgová, Tatiana Červeňová, Erika Halašová, Ján Lehotský
Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid derived in methionine metabolism. The increased level of Hcy in plasma, hyperhomocysteinemia, is considered to be an independent risk factor for cardio and cerebrovascular diseases. However, it is still not clear if Hcy is a marker or a causative agent of diseases. More and more research data suggest that Hcy is an important indicator for overall health status. This review represents the current understanding of molecular mechanism of Hcy metabolism and its link to hyperhomocysteinemia-related pathologies in humans...
October 20, 2016: International Journal of Molecular Sciences
M Kvandová, M Majzúnová, I Dovinová
The peroxisome proliferator-activated receptors (PPAR) belong to the nuclear superfamily of ligand-activated transcription factors. PPARgamma acts as a nutrient sensor that regulates several homeostatic functions. Its disruption can lead to vascular pathologies, disorders of fatty acid/lipid metabolism and insulin resistance. PPARgamma can modulate several signaling pathways connected with blood pressure regulation. Firstly, it affects the insulin signaling pathway and endothelial dysfunction by modulation of expression and/or phosphorylation of signaling molecules through the PI3K/Akt/eNOS or MAPK/ET-1 pathways...
October 24, 2016: Physiological Research
Kyle J Seamon, Namandje N Bumpus, James T Stivers
Sterile Alpha Motif and HD Domain Protein 1 (SAMHD1) is a unique enzyme that has important roles in nucleic acid metabolism, viral restriction, and the pathogenesis of autoimmune diseases and cancer. Although much attention has been focused on its dNTP triphosphohydrolase activity in viral restriction and disease, SAMHD1 also binds to single-stranded RNA and DNA. Here we utilize a UV crosslinking method using 5-bromodeoxyuridine-substituted oligonucleotides coupled with high-resolution mass spectrometry (HRMS) to identify the binding site for single-stranded nucleic acids (ssNA) on SAMHD1...
October 24, 2016: Biochemistry
Yana K Rennie, Patrick J McIntyre, Tito Akindele, Richard Bayliss, Andrew G Jamieson
Inhibition of protein kinases using ATP-competitive compounds is an important strategy in drug discovery. In contrast, the allosteric regulation of kinases through the disruption of protein-protein interactions has not been widely adopted, despite the potential for selective targeting. Aurora-A kinase regulates mitotic entry and mitotic spindle assembly, and is a promising target for anti-cancer therapy. The microtubule-associated protein TPX2 activates Aurora-A through binding to two sites. Aurora-A recognition is mediated by two motifs within the first 43 residues of TPX2, connected by a flexible linker...
October 24, 2016: ACS Chemical Biology
Sho-Ichi Yamagishi, Takanori Matsui, Yuji Ishibashi, Fumiyuki Isami, Yumi Abe, Tatsuya Sakaguchi, Yuichiro Higashimoto
Reducing sugars can react non-enzymatically with amino groups of proteins and lipids to form irreversibly cross-linked macroprotein derivatives called as advanced glycation end products (AGEs). Cross-linking modification of extracellular matrix proteins by AGEs deteriorate their tertiary structural integrity and function, contributing to aging-related organ damage and diabetes-associated complications, such as cardiovascular disease (CVD). Moreover, engagement of receptor for AGEs, RAGE with the ligands evoke oxidative stress generation and inflammatory, thrombotic and fibrotic reactions in various kinds of tissues, further exacerbating the deleterious effects of AGEs on multiple organ systems...
October 21, 2016: Current Pharmaceutical Design
Nurul Iman A Kameel, Adawiyah Suriza Shuib, Saad Tayyab
Acid denaturation of champedak galactose-binding (CGB) lectin was studied in the pH range, 7.0-1.0 using intrinsic fluorescence and ANS fluorescence measurements. The lectin remained stable up to pH 5.0 and showed local disordering in the vicinity of the protein fluorophores within the pH range, 5.0-3.5. Decrease in the pH from pH 3.5 to pH 2.5 led to structural transition, marked by the decrease in the intrinsic fluorescence and increase in the ANS fluorescence signals. This can be ascribed to the dissociation of the tetrameric lectin into monomeric forms...
October 19, 2016: Protein and Peptide Letters
Lena Constantin
MicroRNAs (miRNAs) are a class of small non-coding RNA molecules with wide-ranging and subtle effects on protein production. Their activity during the development of the cerebellum provides a valuable exemplar of how non-coding molecules may assist the development and function of the central nervous system and drive neurodevelopmental disorders. Three distinct aspects of miRNA contribution to early cerebellar development will here be reviewed. Aspects are the establishment of the cerebellar anlage, the generation and maturation of at least two principal cell types of the developing cerebellar microcircuit, and the etiology and early progression of autism spectrum disorder...
October 24, 2016: Molecular Neurobiology
Anne S Bie, Paula Fernandez-Guerra, Rune I D Birkler, Shahar Nisemblat, Dita Pelnena, Xinping Lu, Joshua L Deignan, Hane Lee, Naghmeh Dorrani, Thomas J Corydon, Johan Palmfeldt, Liga Bivina, Abdussalam Azem, Kristin Herman, Peter Bross
We here report molecular investigations of a missense mutation in the HSPE1 gene encoding the HSP10 subunit of the HSP60/ HSP10 chaperonin complex that assists protein folding in the mitochondrial matrix. The mutation was identified in an infant who came to clinical attention due to infantile spasms at 3 months of age. Clinical exome sequencing revealed heterozygosity for a HSPE1 NM_002157.2:c.217C>T de novo mutation causing replacement of leucine with phenylalanine at position 73 of the HSP10 protein. This variation has never been observed in public exome sequencing databases or the literature...
2016: Frontiers in Molecular Biosciences
Benxu Cheng, Pinki Anand, Anxiu Kuang, Feroz Akhtar, Virginia L Scofield
Ubiquitin proteasome system (UPS) dysfunction has been implicated in the development of many neuronal disorders, including Parkinson's disease (PD). Previous studies focused on individual neuroprotective agents and their respective abilities to prevent neurotoxicity following a variety of toxic insults. However, the effects of the antioxidant N-acetylcysteine (NAC) on proteasome impairment-induced apoptosis have not been well characterized in human neuronal cells. The aim of this study was to determine whether cotreatment of NAC and insulin-like growth factor-1 (IGF-1) efficiently protected against proteasome inhibitor-induced cytotoxicity in SH-SY5Y cells...
2016: Parkinson's Disease
Nadine Griesche, Judith Schilling, Stephanie Weber, Marlena Rohm, Verena Pesch, Frank Matthes, Georg Auburger, Sybille Krauss
Expansion of CAG repeats, which code for the disease-causing polyglutamine protein, is a common feature in polyglutamine diseases. RNA-mediated mechanisms that contribute to neuropathology in polyglutamine diseases are important. RNA-toxicity describes a phenomenon by which the mutant CAG repeat RNA recruits RNA-binding proteins, thereby leading to aberrant function. For example the MID1 protein binds to mutant huntingtin (HTT) RNA, which is linked to Huntington's disease (HD), at its CAG repeat region and induces protein synthesis of mutant protein...
2016: Frontiers in Cellular Neuroscience
Dan Wang, Yi-Ming Chen, Miao-Hua Ruan, Ai-Hua Zhou, Yan Qian, Chao Chen
Elevated plasma levels of homocysteine have been implicated in neurodevelopmental and neurodegenerative disorders in human studies. Although the molecular mechanisms underlying the effects of homocysteine (Hcy) cytotoxicity on the nervous system are not yet fully unknown, induction of DNA interstrand cross-links and inhibition of neural stem cells (NSCs) survival may be involved. The objective of our study was to investigate the effects of Hcy on DNA interstrand cross-links in NSCs, and to explore its possible mechanisms...
October 20, 2016: Neuroscience Letters
Vidya Narayanaswami, Linda P Dwoskin
Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior...
October 20, 2016: Pharmacology & Therapeutics
Vaida Juozapaitienė, Brigita Bartkutė, Vilma Michailovienė, Audrius Zakšauskas, Lina Baranauskienė, Sandra Satkūnė, Daumantas Matulis
Human carbonic anhydrase XIV (CA XIV), a transmembrane protein, highly expressed in the central nervous system, is difficult to recombinantly express and purify in large scale for the measurements of inhibitor binding and drug design. CA XIV belongs to the family of twelve catalytically active CA isoforms in the human body. Disorders in the expression of CA XIV cause serious diseases and CA XIV has been described as a possible drug target for the treatment of epilepsy, some retinopathies, and skin tumors. In this study, the effect of different promoters, E...
October 20, 2016: Journal of Biotechnology
Naif O Al-Harbi, Ahmed Nadeem, Mohammed M Al-Harbi, Khairy M A Zoheir, Mushtaq A Ansari, Ahmed M El-Sherbeeny, Khalid M Alanazi, Moureq R Alotaibi, Sheikh F Ahmad
Psoriatic inflammation has been shown to be associated with cardiovascular dysfunction and systemic inflammation. Recently, psoriasis has also been linked to hepatic disorders, however underlying mechanism connecting the two are unknown. IL-17A being a central pro-inflammatory cytokine in the pathogenesis of psoriasis may be involved in hepatic inflammation through its receptor and downward signaling; however so far no study has investigated IL-17A related signaling in the liver during psoriasis in a murine model...
October 18, 2016: Immunobiology
Lena Diekmann, Marc Behrendt, Mahdi Amiri, Hassan Y Naim
BACKGROUND: Lactase phlorizin-hydrolase (LPH) is a membrane anchored type I glycoprotein of the intestinal epithelium that is composed of four homologous structural domains. The role of each distinct domain in the intramolecular organization and function of LPH is not completely understood. METHODS: Here, we analyzed the early events of LPH biosynthesis and trafficking by directed restructuring of the domain compositions. RESULTS: Removal of domain I (LPH∆1) results in a malfolded ER-localized protein...
October 21, 2016: Biochimica et Biophysica Acta
Keqiang Xie, Lesley A Colgan, Maria T Dao, Brian S Muntean, Laurie P Sutton, Cesare Orlandi, Sanford L Boye, Shannon E Boye, Chien-Cheng Shih, Yuqing Li, Baoji Xu, Roy G Smith, Ryohei Yasuda, Kirill A Martemyanov
It is well recognized that G-protein-coupled receptors (GPCRs) can activate Ras-regulated kinase pathways to produce lasting changes in neuronal function. Mechanisms by which GPCRs transduce these signals and their relevance to brain disorders are not well understood. Here, we identify a major Ras regulator, neurofibromin 1 (NF1), as a direct effector of GPCR signaling via Gβγ subunits in the striatum. We find that binding of Gβγ to NF1 inhibits its ability to inactivate Ras. Deletion of NF1 in striatal neurons prevents the opioid-receptor-induced activation of Ras and eliminates its coupling to Akt-mTOR-signaling pathway...
October 18, 2016: Current Biology: CB
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