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Intrinsically disordered protein

Sailen Barik
The two classical immunophilin families, found essentially in all living cells, are: cyclophilin (CYN) and FK506-binding protein (FKBP). We previously reported a novel class of immunophilins that are natural chimera of these two, which we named dual-family immunophilin (DFI). The DFIs were found in either of two conformations: CYN-linker-FKBP (CFBP) or FKBP-3TPR-CYN (FCBP). While the 3TPR domain can serve as a flexible linker between the FKBP and CYN modules in the FCBP-type DFI, the linker sequences in the CFBP-type DFIs are relatively short, diverse in sequence, and contain no discernible motif or signature...
2018: Computational and Structural Biotechnology Journal
Aiko Machiya, Sho Tsukamoto, Satoshi Ohte, Mai Kuratani, Mai Fujimoto, Keigo Kumagai, Kenji Osawa, Naoto Suda, Alex N Bullock, Takenobu Katagiri
Various substitution mutations in ALK2, a transmembrane serine/threonine kinase receptor for bone morphogenetic proteins (BMPs), have been identified in patients with genetic disorders such as fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine glioma (DIPG) and heart defects. In this study, we characterized the ALK2 mutants R258G, G328V and F246Y, which were identified in patients with severe FOP, DIPG and unusual hereditary skeletal dysplasia, respectively. Both R258G and G328V were gain-of-function mutations, but F246Y was equivalent to wild-type ALK2...
March 15, 2018: Bone
Evdokiya Salamanova, Joana Costeira-Paulo, Kyou-Hoon Han, Do-Hyoung Kim, Lennart Nilsson, Anthony P H Wright
BACKGROUND: Adaptive mutations that alter protein functionality are enriched within intrinsically disordered protein regions (IDRs), thus conformational flexibility correlates with evolvability. Pre-structured motifs (PreSMos) with transient propensity for secondary structure conformation are believed to be important for IDR function. The glucocorticoid receptor tau1core transcriptional activation domain (GR tau1core) domain contains three α-helical PreSMos in physiological buffer conditions...
March 14, 2018: Biochimica et Biophysica Acta
Sankar Basu, Parbati Biswas
Intrinsically Disordered Proteins (IDPs) are enriched in charged and polar residues; and, therefore, electrostatic interactions play a predominant role in their dynamics. In order to remain multi-functional and exhibit their characteristic binding promiscuity, they need to retain considerable dynamic flexibility. At the same time, they also need to accommodate a large number of oppositely charged residues, which eventually lead to the formation of salt-bridges, imparting local rigidity. The formation of salt-bridges therefore opposes the desired dynamic flexibility...
March 13, 2018: Biochimica et Biophysica Acta
João Henriques, Lise Arleth, Kresten Lindorff-Larsen, Marie Skepö
Solution techniques such as small-angle X-ray scattering (SAXS) play a central role in structural studies of intrinsically disordered proteins (IDPs), yet, due to low-resolution, it is generally necessary to combine SAXS with additional experimental sources of data and to use molecular simulations. Computational methods for the calculation of theoretical SAXS intensity profiles can be separated into two groups, depending on whether the solvent is modeled implicitly as continuous electron density or considered explicitly...
March 13, 2018: Journal of Molecular Biology
Beate Hoffmann, Frank Löhr, Aisha Laguerre, Frank Bernhard, Volker Dötsch
Preparation of a protein sample for liquid-state nuclear magnetic resonance (NMR) spectroscopy analysis requires optimization of many parameters. This review describes labeling strategies for obtaining assignments of protein resonances. Particular emphasis is placed on the advantages of cell-free protein production, which enables exclusive labeling of the protein of interest, thereby simplifying downstream processing steps and increasing the availability of different labeling strategies for a target protein...
April 2018: Progress in Nuclear Magnetic Resonance Spectroscopy
Robert I Cukier
Intrinsically disordered proteins (IDPs) sample a diverse conformational space. They are important to signaling and regulatory pathways in cells. An entropy penalty must be payed when an IDP becomes ordered upon interaction with another protein or a ligand. Thus, the degree of conformational disorder of an IDP is of interest. We create a dichotomic Markov model that can explore entropic features of an IDP. The Markov condition introduces local (neighbor residues in a protein sequence) rotamer dependences that arise from van der Waals and other chemical constraints...
March 14, 2018: Journal of Chemical Physics
Changqing Lu, Lihua Dong, Hui Zhou, Qianmei Li, Guojiao Huang, Shu Jun Bai, Linchuan Liao
Oligodendrocytes are the myelin-producing cells of the central nervous system (CNS). A variety of brain disorders from "classical" demyelinating diseases, such as multiple sclerosis, stroke, schizophrenia, depression, Down syndrome and autism, are shown myelination defects. Oligodendrocyte myelination is regulated by a complex interplay of intrinsic, epigenetic and extrinsic factors. Gpr17 (G protein-coupled receptor 17) is a G protein-coupled receptor, and has been identified to be a regulator for oligodendrocyte development...
March 14, 2018: Scientific Reports
Anthony Banks, Sanbo Qin, Kevin L Weiss, Christopher B Stanley, Huan-Xiang Zhou
Conformational malleability allows intrinsically disordered proteins (IDPs) to respond agilely to their environments, such as nonspecifically interacting with in vivo bystander macromolecules (or crowders). Previous studies have emphasized conformational compaction of IDPs due to steric repulsion by macromolecular crowders, but effects of soft attraction are largely unexplored. Here we studied the conformational ensembles of the IDP FlgM in both polymer and protein crowders by small-angle neutron scattering...
March 13, 2018: Biophysical Journal
Sneha Munshi, Soundhararajan Gopi, Sandhyaa Subramanian, Luis A Campos, Athi N Naganathan
The amplitude of thermodynamic fluctuations in biological macromolecules determines their conformational behavior, dimensions, nature of phase transitions and effectively their specificity and affinity, thus contributing to fine-tuned molecular recognition. Unique among large-scale conformational changes in proteins are temperature-induced collapse transitions in intrinsically disordered proteins (IDPs). Here, we show that CytR DNA-binding domain, an IDP that folds on binding DNA, undergoes a coil-to-globule transition with temperature in the absence of DNA while exhibiting energetically decoupled local and global structural rearrangements, and maximal thermodynamic fluctuations at the optimal bacterial growth temperature...
March 10, 2018: Nucleic Acids Research
Yanhua Ouyang, Likun Zhao, Zhuqing Zhang
Intrinsically disordered regions (IDRs) or proteins (IDPs), which play crucial biological functions in essential biological processes of life, do not have well-defined secondary or tertiary structures when isolated in solution. The highly dynamic properties and conformational heterogeneity of IDPs make them challenging to study with traditional experimental techniques. As a powerful complementary tool for experiments, all-atom molecular dynamics simulation can obtain detailed conformational information on IDPs, but the limitation of force field accuracy is a challenge for reproducing IDP conformers...
March 14, 2018: Physical Chemistry Chemical Physics: PCCP
Myungchul Song, Kyunghee Song, Sunghee Kim, Jinyoung Lee, Sueyun Hwang, Chingtack Han
Caenorhabditis elegans C09F5.1 is a nematode-specific gene that encodes a type II transmembrane protein containing the BRICHOS domain. The gene was isolated as a heat-sensitive mutant, but the function of the protein remained unclear. We examined the expression pattern and subcellular localization of C09F5.1 as well as its roles in thermotolerance and chaperone function. Expression of C09F5.1 under heat shock conditions was induced in a heat shock factor 1 (HSF-1)-dependent manner. However, under normal growth conditions, most cells types exposed to mechanical stimuli expressed C09F5...
March 13, 2018: Genes
Patricia Santofimia-Castaño, Bruno Rizzuti, Olga Abián, Adrián Velázquez-Campoy, Juan L Iovanna, José L Neira
BACKGROUND: NUPR1 is a multifunctional intrinsically disordered protein (IDP) involved, among other functions, in chromatin remodelling, and development of pancreatic ductal adenocarcinoma (PDAC). It interacts with several biomolecules through hydrophobic patches around residues Ala33 and Thr68. The drug trifluoperazine (TFP), which hampers PDAC development in xenografted mice, also binds to those regions. Because of the large size of the hot-spot interface of NUPR1, small molecules could not be adequate to modulate its functions...
March 9, 2018: Biochimica et Biophysica Acta
Liying Li, J P McGinnis, Kausik Si
Prion-like proteins overlap with intrinsically disordered and low-complexity sequence families. These proteins are widespread, especially among mRNA-binding proteins. A salient feature of these proteins is the ability to form protein assemblies with distinct biophysical and functional properties. While prion-like proteins are involved in myriad of cellular processes, we propose potential roles for protein assemblies in regulated protein synthesis. Since proteins are the ultimate functional output of gene expression, when, where, and how much of a particular protein is made dictates the functional state of a cell...
March 9, 2018: Trends in Cell Biology
Xuewei Dong, Qin Qiao, Zhenyu Qian, Guanghong Wei
The amyloid deposits of human islet amyloid polypeptide (hIAPP) are found in type II diabetes patients. hIAPP monomer is intrinsically disordered in solution, whereas it can form amyloid fibrils both in vivo and in vitro. Extensive evidence suggests that hIAPP causes the disruption of cellular membrane, and further induces cytotoxicity and the death of islet β-cells in pancreas. The presence of membrane also accelerates the hIAPP fibril formation. hIAPP oligomers and protofibrils in the early stage of aggregation were reported to be the most cytotoxic, disrupting the membrane integrity and giving rise to the pathological process...
March 9, 2018: Biochimica et Biophysica Acta
Or Szekely, Gregory Lars Olsen, Isabella Caterina Felli, Lucio Frydman
This study demonstrates the usefulness derived from relying on hyperpolarized water obtained by dissolution DNP, for site-resolved biophysical NMR studies of intrinsically disordered proteins. Thanks to the facile amide-solvent exchange experienced by protons in these proteins, 2D NMR experiments that like HMQC rely on the polarization of the amide protons, can be enhanced using hyperpolarized water by several orders of magnitude over their conventional counterparts. Optimizations of the DNP procedure and of the subsequent injection into the protein sample are necessary to achieve these gains while preserving state-of-the-art resolution; procedures enabling this transfer of the hyperpolarized water and the achievement of foamless hyperpolarized protein solutions, are here demonstrated...
March 12, 2018: Analytical Chemistry
Vijayaraghavan Rangachari, Dexter N Dean, Pratip Rana, Ashwin Vaidya, Preetam Ghosh
Self-templating propagation of protein aggregate conformations is increasingly becoming a significant factor in many neurological diseases. In Alzheimer disease (AD), intrinsically disordered amyloid-β (Aβ) peptides undergo aggregation that is sensitive to environmental conditions. High-molecular weight aggregates of Aβ that form insoluble fibrils are deposited as senile plaques in AD brains. However, low-molecular weight aggregates called soluble oligomers are known to be the primary toxic agents responsible for neuronal dysfunction...
March 8, 2018: Biochimica et Biophysica Acta
Thuy P Dao, Regina-Maria Kolaitis, Hong Joo Kim, Kevin O'Donovan, Brian Martyniak, Erica Colicino, Heidi Hehnly, J Paul Taylor, Carlos A Castañeda
Under stress, certain eukaryotic proteins and RNA assemble to form membraneless organelles known as stress granules. The most well-studied stress granule components are RNA-binding proteins that undergo liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by intrinsically disordered low-complexity domains (LCDs). Here we show that stress granules include proteasomal shuttle factor UBQLN2, an LCD-containing protein structurally and functionally distinct from RNA-binding proteins. In vitro, UBQLN2 exhibits LLPS at physiological conditions...
February 23, 2018: Molecular Cell
Max V Staller, Alex S Holehouse, Devjanee Swain-Lenz, Rahul K Das, Rohit V Pappu, Barak A Cohen
Transcriptional activation domains are essential for gene regulation, but their intrinsic disorder and low primary sequence conservation have made it difficult to identify the amino acid composition features that underlie their activity. Here, we describe a rational mutagenesis scheme that deconvolves the function of four activation domain sequence features-acidity, hydrophobicity, intrinsic disorder, and short linear motifs-by quantifying the activity of thousands of variants in vivo and simulating their conformational ensembles using an all-atom Monte Carlo approach...
March 1, 2018: Cell Systems
Edgar E Boczek, Simon Alberti
Small heat shock proteins (sHsps) are adenosine triphosphate-independent chaperones that protect cells from misfolded proteins. In this issue, Grousl et al. (2018. J. Cell Biol. show that the yeast sHsp Hsp42 uses a prion-like intrinsically disordered domain to bind and sequester misfolded proteins in protein deposition sites.
March 9, 2018: Journal of Cell Biology
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