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Intrinsically disordered protein

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https://www.readbyqxmd.com/read/29782836/dancing-with-the-diva-hsp90-client-interactions
#1
REVIEW
Martina Radli, Stefan G D Rüdiger
The molecular chaperone Hsp90 is involved in the folding, maturation and degradation of a large number structurally and sequentially unrelated clients, often connected to serious diseases. Elucidating the principles of how Hsp90 recognises this large variety of substrates is essential for comprehending the mechanism of this chaperone machinery, as well as it is a prerequisite for the design of client specific drugs targeting Hsp90. Here, we discuss the recent progress in understanding the substrate recognition principles of Hsp90 and its implications for the role of Hsp90 in the lifecycle of (signalling) molecules...
May 18, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29782835/multi-pronged-interactions-underlie-inhibition-of-%C3%AE-synuclein-aggregation-by-%C3%AE-synuclein
#2
Jonathan K Williams, Xue Yang, Tamr B Atieh, Michael P Olson, Sagar D Khare, Jean Baum
The intrinsically disordered protein β-synuclein is known to inhibit the aggregation of its intrinsically disordered homolog, α-synuclein, which is implicated in Parkinson's disease. While β-synuclein itself does not form fibrils at the cytoplasmic pH7.4, alteration of pH and other environmental perturbations are known to induce its fibrilization. However, the sequence and structural determinants of β-synuclein inhibition and self-aggregation are not well understood. We have utilized a series of domain-swapped chimeras of α-synuclein and β-synuclein to probe the relative contributions of the N-terminal, C-terminal and the central Non-Amyloid-β Component (NAC) domains to the inhibition of α-synuclein aggregation...
May 18, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29780502/the-impact-of-o-glycan-chemistry-on-the-stability-of-intrinsically-disordered-proteins
#3
Erica T Prates, Xiaoyang Guan, Yaohao Li, Xinfeng Wang, Patrick K Chaffey, Munir S Skaf, Michael F Crowley, Zhongping Tan, Gregg T Beckham
Protein glycosylation is a diverse post-translational modification that serves myriad biological functions. O -linked glycans in particular vary widely in extent and chemistry in eukaryotes, with secreted proteins from fungi and yeast commonly exhibiting O -mannosylation in intrinsically disordered regions of proteins, likely for proteolysis protection, among other functions. However, it is not well understood why mannose is often the preferred glycan, and more generally, if the neighboring protein sequence and glycan have coevolved to protect against proteolysis in glycosylated intrinsically disordered proteins (IDPs)...
April 21, 2018: Chemical Science
https://www.readbyqxmd.com/read/29780404/intrinsic-disorder-and-posttranslational-modifications-the-darker-side-of-the-biological-dark-matter
#4
REVIEW
April L Darling, Vladimir N Uversky
Intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) are functional proteins and domains that devoid stable secondary and/or tertiary structure. IDPs/IDPRs are abundantly present in various proteomes, where they are involved in regulation, signaling, and control, thereby serving as crucial regulators of various cellular processes. Various mechanisms are utilized to tightly regulate and modulate biological functions, structural properties, cellular levels, and localization of these important controllers...
2018: Frontiers in Genetics
https://www.readbyqxmd.com/read/29777197/the-transition-state-structure-for-binding-between-taz1-of-cbp-and-the-disordered-hif-1%C3%AE-cad
#5
Ida Lindström, Eva Andersson, Jakob Dogan
Intrinsically disordered proteins (IDPs) are common in eukaryotes. However, relatively few experimental studies have addressed the nature of the rate-limiting transition state for the coupled binding and folding reactions involving IDPs. By using site-directed mutagenesis in combination with kinetics measurements we have here characterized the transition state for binding between the globular TAZ1 domain of CREB binding protein and the intrinsically disordered C-terminal activation domain of Hif-1α (Hif-1α CAD)...
May 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29763584/equation-chapter-1-section-1sequence-to-conformation-relationships-of-disordered-regions-tethered-to-folded-domains-of-proteins
#6
Anuradha Mittal, Alex S Holehouse, Megan C Cohan, Rohit V Pappu
Intrinsically disordered proteins and regions (IDPs / IDRs) are characterized by well-defined sequence-to-conformation relationships (SCRs). These relationships refer to the sequence-specific preferences for average sizes, shapes, residue-specific secondary structure propensities, and amplitudes of multiscale conformational fluctuations. SCRs are discerned from the sequence-specific conformational ensembles of IDPs. A vast majority of IDPs are actually tethered to folded domains (FDs). This raises the question of whether or not SCRs inferred for IDPs are applicable to IDRs tethered to folded domains...
May 12, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29761107/intramolecular-fuzzy-interactions-involving-intrinsically-disordered-domains
#7
REVIEW
Miguel Arbesú, Guillermo Iruela, Héctor Fuentes, João M C Teixeira, Miquel Pons
Structural disorder is an essential ingredient for function in many proteins and protein complexes. Fuzzy complexes describe the many instances where disorder is maintained as a critical element of protein interactions. In this minireview we discuss how intramolecular fuzzy interactions function in signaling complexes. Focussing on the Src family of kinases, we argue that the intrinsically disordered domains that are unique for each of the family members and display a clear fingerprint of long range interactions in Src, might have critical roles as functional sensor or effectors and mediate allosteric communication via fuzzy interactions...
2018: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/29759983/high-throughput-discovery-of-functional-disordered-regions-investigation-of-transactivation-domains
#8
Charles Nj Ravarani, Tamara Y Erkina, Greet De Baets, Daniel C Dudman, Alexandre M Erkine, M Madan Babu
Over 40% of proteins in any eukaryotic genome encode intrinsically disordered regions (IDRs) that do not adopt defined tertiary structures. Certain IDRs perform critical functions, but discovering them is non-trivial as the biological context determines their function. We present IDR-Screen, a framework to discover functional IDRs in a high-throughput manner by simultaneously assaying large numbers of DNA sequences that code for short disordered sequences. Functionality-conferring patterns in their protein sequence are inferred through statistical learning...
May 14, 2018: Molecular Systems Biology
https://www.readbyqxmd.com/read/29758263/page4-and-conformational-switching-insights-from-molecular-dynamics-simulations-and-implications-for-prostate-cancer
#9
Xingcheng Lin, Susmita Roy, Mohit Kumar Jolly, Federico Bocci, Nicholas P Schafer, Min-Yeh Tsai, Yihong Chen, Yanan He, Alexander Grishaev, Keith Weninger, John Orban, Prakash Kulkarni, Govindan Rangarajan, Herbert Levine, José N Onuchic
Prostate-Associated Gene 4 (PAGE4) is an intrinsically disordered protein (IDP) implicated in prostate cancer. The stress-response kinase Homeodomain-Interacting Protein Kinase 1 (HIPK1) phosphorylates two residues in PAGE4, serine 9 and threonine 51. Phosphorylation of these two residues facilitates the interaction of PAGE4 with Activator Protein-1 (AP-1) transcription factor complex to potentiate AP-1's activity. In contrast, hyperphosphorylation of PAGE4 by CDC-Like Kinase 2 (CLK2) attenuates this interaction with AP-1...
May 11, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29754825/structure-of-human-nata-and-its-regulation-by-the-huntingtin-interacting-protein-hypk
#10
Leah Gottlieb, Ronen Marmorstein
Co-translational N-terminal protein acetylation regulates many protein functions including degradation, folding, interprotein interactions, and targeting. Human NatA (hNatA), one of six conserved metazoan N-terminal acetyltransferases, contains Naa10 catalytic and Naa15 auxiliary subunits, and associates with the intrinsically disordered Huntingtin yeast two-hybrid protein K (HYPK). We report on the crystal structures of hNatA and hNatA/HYPK, and associated biochemical and enzymatic analyses. We demonstrate that hNatA contains unique features: a stabilizing inositol hexaphosphate (IP6 ) molecule and a metazoan-specific Naa15 domain that mediates high-affinity HYPK binding...
April 23, 2018: Structure
https://www.readbyqxmd.com/read/29753880/ligand-interactions-and-the-protein-order-disorder-energetic-continuum
#11
REVIEW
Mahdi Muhammad Moosa, Josephine C Ferreon, Allan Chris M Ferreon
Intrinsically disordered proteins as computationally predicted account for ∼1/3 of eukaryotic proteomes, are involved in a plethora of biological functions, and have been linked to several human diseases as a result of their dysfunctions. Here, we present a picture wherein an energetic continuum describes protein structural and conformational propensities, ranging from the hyperstable folded proteins on one end to the hyperdestabilized and sometimes functionally disordered proteins on the other. We distinguish between proteins that are folding-competent but disordered because of marginal stability and those that are disordered due mainly to the absence of folding code-completing structure-determining interactions, and postulate that disordered proteins that are unstructured by way of partial population of protein denatured states represent a sizable proportion of the proteome...
May 12, 2018: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/29751043/tauroursodeoxycholic-acid-attenuates-gentamicin-induced-cochlear-hair-cell-death-in-vitro
#12
Zhanwei Jia, Qiang He, Chunguang Shan, Fengyi Li
Gentamycin is one of the most clinically used aminoglycoside antibiotics which induce intrinsic apoptosis of hair cells. Tauroursodeoxycholic acid (TUDCA) is known as safe cell-protective agent in disorders associated with apoptosis. We aimed to investigate the protective effects of TUDCA against gentamicin-induced ototoxicity. House Ear Institute-Organ of Corti 1(HEI-OC1) cells and explanted cochlear tissue were treated with gentamicin and TUDCA, followed by serial analyses including cell viability assay, hair cell staining, qPCR, ELISA and western blotting to determine the cell damage by the parameters relevant to cell apoptosis and endoplasmic reticulum stress...
May 8, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29748917/taurine-protects-from-pentylenetetrazole-induced-behavioral-and-neurochemical-changes-in-zebrafish
#13
Barbara D Fontana, Paola R Ziani, Julia Canzian, Nathana J Mezzomo, Talise E Müller, Matheus M Dos Santos, Vania L Loro, Nilda V Barbosa, Carlos F Mello, Denis B Rosemberg
Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures, which culminate in various neurobehavioral and neurochemical changes. Taurine (TAU) is an amino sulfonic acid which acts an endogenous inhibitory neuromodulator. Moreover, TAU displays intrinsic antioxidant activity, contributing to its beneficial actions in the CNS. Here, we evaluated whether TAU pretreatment protects from pentylenetetrazole (PTZ)-induced behavioral alterations and oxidative stress-related parameters in zebrafish brain tissue...
May 11, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29746250/cellular-assays-for-studying-the-fe-s-cluster-containing-base-excision-repair-glycosylase-mutyh-and-homologs
#14
Chandrima Majumdar, Nicole N Nuñez, Alan G Raetz, Cindy Khuu, Sheila S David
Many DNA repair enzymes, including the human adenine glycosylase MUTYH, require iron-sulfur (Fe-S) cluster cofactors for DNA damage recognition and subsequent repair. MUTYH prokaryotic and eukaryotic homologs are a family of adenine (A) glycosylases that cleave A when mispaired with the oxidatively damaged guanine lesion, 8-oxo-7,8-dihydroguanine (OG). Faulty OG:A repair has been linked to the inheritance of missense mutations in the MUTYH gene. These inherited mutations can result in the onset of a familial colorectal cancer disorder known as MUTYH-associated polyposis (MAP)...
2018: Methods in Enzymology
https://www.readbyqxmd.com/read/29738715/phosphorylation-mediated-clearance-of-amyloid-like-assemblies-in-meiosis
#15
Kayla Carpenter, Rachel Brietta Bell, Julius Yunus, Angelika Amon, Luke Edwin Berchowitz
Amyloids are fibrous protein assemblies that are often described as irreversible and intrinsically pathogenic. However, yeast cells employ amyloid-like assemblies of the RNA-binding protein Rim4 to control translation during meiosis. Here, we show that multi-site phosphorylation of Rim4 is critical for its regulated disassembly and degradation and that failure to clear Rim4 assemblies interferes with meiotic progression. Furthermore, we identify the protein kinase Ime2 to bring about Rim4 clearance via phosphorylation of Rim4's intrinsically disordered region...
May 7, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29738494/toward-the-discovery-of-a-novel-class-of-yap%C3%A2-tead-interaction-inhibitors-by-virtual-screening-approach-targeting-yap%C3%A2-tead-protein%C3%A2-protein-interface
#16
Floriane Gibault, Mathilde Coevoet, Manon Sturbaut, Amaury Farce, Nicolas Renault, Frédéric Allemand, Jean-François Guichou, Anne-Sophie Drucbert, Catherine Foulon, Romain Magnez, Xavier Thuru, Matthieu Corvaisier, Guillemette Huet, Philippe Chavatte, Patricia Melnyk, Fabrice Bailly, Philippe Cotelle
Intrinsically disordered protein YAP (yes-associated protein) interacts with TEADs transcriptional factors family (transcriptional enhancer associated domain) creating three interfaces. Interface 3, between the Ω-loop of YAP and a shallow pocket of TEAD was identified as the most important TEAD zone for YAP-TEAD interaction. Using the first X-ray structure of the hYAP50⁻71 -hTEAD1209⁻426 complex (PDB 3KYS) published in 2010, a protein-protein interaction inhibitors-enriched library (175,000 chemical compounds) was screened against this hydrophobic pocket of TEAD...
May 8, 2018: Cancers
https://www.readbyqxmd.com/read/29735729/ensemble-allosteric-model-energetic-frustration-within-the-intrinsically-disordered-glucocorticoid-receptor
#17
REVIEW
Jordan T White, Jing Li, Emily Grasso, James O Wrabl, Vincent J Hilser
Allostery is an important regulatory phenomenon enabling precise control of biological function. Initial understanding of allostery was gained from seminal work on conformational changes exhibited by structured proteins. Within the last decade, protein allostery has also been demonstrated to occur within intrinsically disordered proteins. This emerging concept of disorder-mediated allostery can be usefully understood in the context of a thermodynamic ensemble. The advantage of this ensemble allosteric model is that it unifies the explanations of allostery occurring within both structured and disordered proteins...
June 19, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29734867/composition-related-structural-transition-of-random-peptides-insight-into-the-boundary-between-intrinsically-disordered-proteins-and-folded-proteins
#18
Wen-Bin Kang, Chuan He, Zhen-Xing Liu, Jun Wang, Wei Wang
Previous studies based on bioinformatics showed that there is a sharp distinction of structural features and residue composition between the intrinsically disordered proteins and the folded proteins. What induces such a composition-related structural transition? How do various kinds of interactions work in such processes? In this work, we investigate these problems based on a survey on peptides randomly composed of charged residues (including glutamic acids and lysines) and the residues with different hydrophobicity, such as alanines, glycines or phenylalanines...
May 7, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29734798/the-disordered-c-terminus-of-yeast-hsf1-contains-a-cryptic-low-complexity-amyloidogenic-region
#19
Jordi Pujols, Jaime Santos, Irantzu Pallarès, Salvador Ventura
Response mechanisms to external stress rely on networks of proteins able to activate specific signaling pathways to ensure the maintenance of cell proteostasis. Many of the proteins mediating this kind of response contain intrinsically disordered regions, which lack a defined structure, but still are able to interact with a wide range of clients that modulate the protein function. Some of these interactions are mediated by specific short sequences embedded in the longer disordered regions. Because the physicochemical properties that promote functional and abnormal interactions are similar, it has been shown that, in globular proteins, aggregation-prone and binding regions tend to overlap...
May 6, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29734651/acetylation-disfavors-tau-phase-separation
#20
Josephine C Ferreon, Antrix Jain, Kyoung-Jae Choi, Phoebe S Tsoi, Kevin R MacKenzie, Sung Yun Jung, Allan Chris Ferreon
Neuropathological aggregates of the intrinsically disordered microtubule-associated protein Tau are hallmarks of Alzheimer’s disease, with decades of research devoted to studying the protein’s aggregation properties both in vitro and in vivo. Recent demonstrations that Tau is capable of undergoing liquid-liquid phase separation (LLPS) reveal the possibility that protein-enriched phase separated compartments could serve as initiation sites for Tau aggregation, as shown for other amyloidogenic proteins, such as the Fused in Sarcoma protein (FUS) and TAR DNA-binding protein-43 (TDP-43)...
May 4, 2018: International Journal of Molecular Sciences
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