scholarly journals Protein disorder-to-order transition enhances the nucleosome-binding affinity of H1

2020 ◽  
Vol 48 (10) ◽  
pp. 5318-5331 ◽  
Author(s):  
Akshay Sridhar ◽  
Modesto Orozco ◽  
Rosana Collepardo-Guevara
Keyword(s):  
Binding Affinity ◽  
Binding Proteins ◽  
Intrinsically Disordered Proteins ◽  
Order Transition ◽  
Disordered Proteins ◽  
Chromatin Binding ◽  
Intrinsically Disordered ◽  
Terminal Domain ◽  
Wide Range ◽  
Nucleosome Binding

Abstract Intrinsically disordered proteins are crucial elements of chromatin heterogenous organization. While disorder in the histone tails enables a large variation of inter-nucleosome arrangements, disorder within the chromatin-binding proteins facilitates promiscuous binding to a wide range of different molecular targets, consistent with structural heterogeneity. Among the partially disordered chromatin-binding proteins, the H1 linker histone influences a myriad of chromatin characteristics including compaction, nucleosome spacing, transcription regulation, and the recruitment of other chromatin regulating proteins. Although it is now established that the long C-terminal domain (CTD) of H1 remains disordered upon nucleosome binding and that such disorder favours chromatin fluidity, the structural behaviour and thereby the role/function of the N-terminal domain (NTD) within chromatin is yet unresolved. On the basis of microsecond-long parallel-tempering metadynamics and temperature-replica exchange atomistic molecular dynamics simulations of different H1 NTD subtypes, we demonstrate that the NTD is completely unstructured in solution but undergoes an important disorder-to-order transition upon nucleosome binding: it forms a helix that enhances its DNA binding ability. Further, we show that the helical propensity of the H1 NTD is subtype-dependent and correlates with the experimentally observed binding affinity of H1 subtypes, suggesting an important functional implication of this disorder-to-order transition.

scholarly journals Zooming into the Dark Side of Human Annexin-S100 Complexes: Dynamic Alliance of Flexible Partners

2020 ◽  
Vol 21 (16) ◽  
pp. 5879
Author(s):  
Judith Weisz ◽  
Vladimir N. Uversky
Keyword(s):  
Calcium Binding ◽  
Binding Proteins ◽  
Intrinsically Disordered Proteins ◽  
Structural Information ◽  
S100 Proteins ◽  
Disordered Proteins ◽  
Dark Side ◽  
Intrinsically Disordered ◽  
Wide Range ◽  
Ef Hand

Annexins and S100 proteins form two large families of Ca2+-binding proteins. They are quite different both structurally and functionally, with S100 proteins being small (10–12 kDa) acidic regulatory proteins from the EF-hand superfamily of Ca2+-binding proteins, and with annexins being at least three-fold larger (329 ± 12 versus 98 ± 7 residues) and using non-EF-hand-based mechanism for calcium binding. Members of both families have multiple biological roles, being able to bind to a large cohort of partners and possessing a multitude of functions. Furthermore, annexins and S100 proteins can interact with each other in either a Ca2+-dependent or Ca2+-independent manner, forming functional annexin-S100 complexes. Such functional polymorphism and binding indiscrimination are rather unexpected, since structural information is available for many annexins and S100 proteins, which therefore are considered as ordered proteins that should follow the classical “one protein–one structure–one function” model. On the other hand, the ability to be engaged in a wide range of interactions with multiple, often unrelated, binding partners and possess multiple functions represent characteristic features of intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs); i.e., functional proteins or protein regions lacking unique tertiary structures. The aim of this paper is to provide an overview of the functional roles of human annexins and S100 proteins, and to use the protein intrinsic disorder perspective to explain their exceptional multifunctionality and binding promiscuity.

scholarly journals Supramolecular Fuzziness of Intracellular Liquid Droplets: Liquid–Liquid Phase Transitions, Membrane-Less Organelles, and Intrinsic Disorder

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3265 ◽  
Author(s):  
Vladimir N. Uversky
Keyword(s):  
Phase Transitions ◽  
Liquid Phase ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Bacterial Cells ◽  
Liquid Droplets ◽  
Intrinsically Disordered ◽  
Wide Range ◽  
Characteristic Features

Cells are inhomogeneously crowded, possessing a wide range of intracellular liquid droplets abundantly present in the cytoplasm of eukaryotic and bacterial cells, in the mitochondrial matrix and nucleoplasm of eukaryotes, and in the chloroplast’s stroma of plant cells. These proteinaceous membrane-less organelles (PMLOs) not only represent a natural method of intracellular compartmentalization, which is crucial for successful execution of various biological functions, but also serve as important means for the processing of local information and rapid response to the fluctuations in environmental conditions. Since PMLOs, being complex macromolecular assemblages, possess many characteristic features of liquids, they represent highly dynamic (or fuzzy) protein–protein and/or protein–nucleic acid complexes. The biogenesis of PMLOs is controlled by specific intrinsically disordered proteins (IDPs) and hybrid proteins with ordered domains and intrinsically disordered protein regions (IDPRs), which, due to their highly dynamic structures and ability to facilitate multivalent interactions, serve as indispensable drivers of the biological liquid–liquid phase transitions (LLPTs) giving rise to PMLOs. In this article, the importance of the disorder-based supramolecular fuzziness for LLPTs and PMLO biogenesis is discussed.

scholarly journals Chasing coevolutionary signals in intrinsically disordered proteins complexes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Javier A. Iserte ◽  
Tamas Lazar ◽  
Silvio C. E. Tosatto ◽  
Peter Tompa ◽  
Cristina Marino-Buslje
Keyword(s):  
Protein Interactions ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Protein Protein Interactions ◽  
Contact Prediction ◽  
Intrinsically Disordered ◽  
Regulatory Processes ◽  
Wide Range ◽  
Predict Protein Structure ◽  
Biological Interpretation

Abstract Intrinsically disordered proteins/regions (IDPs/IDRs) are crucial components of the cell, they are highly abundant and participate ubiquitously in a wide range of biological functions, such as regulatory processes and cell signaling. Many of their important functions rely on protein interactions, by which they trigger or modulate different pathways. Sequence covariation, a powerful tool for protein contact prediction, has been applied successfully to predict protein structure and to identify protein–protein interactions mostly of globular proteins. IDPs/IDRs also mediate a plethora of protein–protein interactions, highlighting the importance of addressing sequence covariation-based inter-protein contact prediction of this class of proteins. Despite their importance, a systematic approach to analyze the covariation phenomena of intrinsically disordered proteins and their complexes is still missing. Here we carry out a comprehensive critical assessment of coevolution-based contact prediction in IDP/IDR complexes and detail the challenges and possible limitations that emerge from their analysis. We found that the coevolutionary signal is faint in most of the complexes of disordered proteins but positively correlates with the interface size and binding affinity between partners. In addition, we discuss the state-of-art methodology by biological interpretation of the results, formulate evaluation guidelines and suggest future directions of development to the field.

scholarly journals The Disordered Cellular Multi-Tasker WIP and Its Protein–Protein Interactions: A Structural View

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1084 ◽  
Author(s):  
Chana G. Sokolik ◽  
Nasrin Qassem ◽  
Jordan H. Chill
Keyword(s):  
Protein Interactions ◽  
Cell Biology ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Actin Binding ◽  
Structural Description ◽  
Protein Protein Interactions ◽  
Intrinsically Disordered ◽  
Terminal Domain ◽  
Binding Partners

WASp-interacting protein (WIP), a regulator of actin cytoskeleton assembly and remodeling, is a cellular multi-tasker and a key member of a network of protein–protein interactions, with significant impact on health and disease. Here, we attempt to complement the well-established understanding of WIP function from cell biology studies, summarized in several reviews, with a structural description of WIP interactions, highlighting works that present a molecular view of WIP’s protein–protein interactions. This provides a deeper understanding of the mechanisms by which WIP mediates its biological functions. The fully disordered WIP also serves as an intriguing example of how intrinsically disordered proteins (IDPs) exert their function. WIP consists of consecutive small functional domains and motifs that interact with a host of cellular partners, with a striking preponderance of proline-rich motif capable of interactions with several well-recognized binding partners; indeed, over 30% of the WIP primary structure are proline residues. We focus on the binding motifs and binding interfaces of three important WIP segments, the actin-binding N-terminal domain, the central domain that binds SH3 domains of various interaction partners, and the WASp-binding C-terminal domain. Beyond the obvious importance of a more fundamental understanding of the biology of this central cellular player, this approach carries an immediate and highly beneficial effect on drug-design efforts targeting WIP and its binding partners. These factors make the value of such structural studies, challenging as they are, readily apparent.

scholarly journals A Family of Small Intrinsically Disordered Proteins Involved in Flagellum-Dependent Motility inSalmonella enterica

2018 ◽  
Vol 201 (2) ◽  
Author(s):  
Tamiko Oguri ◽  
Youjeong Kwon ◽  
Jerry K. K. Woo ◽  
Gerd Prehna ◽  
Hyun Lee ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Expression Profiles ◽  
Functional Characterization ◽  
Disordered Proteins ◽  
Wild Type ◽  
Content Type ◽  
Cellular Pathway ◽  
Intrinsically Disordered ◽  
Small Proteins ◽  
Wide Range

ABSTRACTBy screening a collection ofSalmonellamutants deleted for genes encoding small proteins of ≤60 amino acids, we identified three paralogous small genes (ymdF,STM14_1829, andyciG) required for wild-type flagellum-dependent swimming and swarming motility. TheymdF,STM14_1829, andyciGgenes encode small proteins of 55, 60, and 60 amino acid residues, respectively. A bioinformatics analysis predicted that these small proteins are intrinsically disordered proteins, and circular dichroism analysis of purified recombinant proteins confirmed that all three proteins are unstructured in solution. A mutant deleted for STM14_1829 showed the most severe motility defect, indicating that among the three paralogs, STM14_1829 is a key protein required for wild-type motility. We determined that relative to the wild type, the expression of the flagellin protein FliC is lower in the ΔSTM14_1829mutant due to the downregulation of theflhDCoperon encoding the FlhDC master regulator. By comparing the gene expression profiles between the wild-type and ΔSTM14_1829strains via RNA sequencing, we found that the gene encoding the response regulator PhoP is upregulated in the ΔSTM14_1829mutant, suggesting the indirect repression of theflhDCoperon by the activated PhoP. Homologs of STM14_1829 are conserved in a wide range of bacteria, includingEscherichia coliandPseudomonas aeruginosa. We showed that the inactivation of STM14_1829 homologs inE. coliandP. aeruginosaalso alters motility, suggesting that this family of small intrinsically disordered proteins may play a role in the cellular pathway(s) that affects motility.IMPORTANCEThis study reports the identification of a novel family of small intrinsically disordered proteins that are conserved in a wide range of flagellated and nonflagellated bacteria. Although this study identifies the role of these small proteins in the scope of flagellum-dependent motility inSalmonella, they likely play larger roles in a more conserved cellular pathway(s) that indirectly affects flagellum expression in the case of motile bacteria. Small intrinsically disordered proteins have not been well characterized in prokaryotes, and the results of our study provide a basis for their detailed functional characterization.

The C-terminal domain of measles virus nucleoprotein belongs to the class of intrinsically disordered proteins that fold upon binding to their physiological partner

2004 ◽  
Vol 99 (2) ◽  
pp. 157-167 ◽  
Author(s):  
Jean-Marie Bourhis ◽  
Kenth Johansson ◽  
Véronique Receveur-Bréchot ◽  
Christopher J. Oldfield ◽  
Keith A. Dunker ◽  
...  
Keyword(s):  
Measles Virus ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Terminal Domain

scholarly journals Intrinsically disordered proteins and structured proteins with intrinsically disordered regions have different functional roles in the cell

2019 ◽  
Author(s):  
Antonio Deiana ◽  
Sergio Forcelloni ◽  
Alessandro Porrello ◽  
Andrea Giansanti
Keyword(s):  
Binding Proteins ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
General Category ◽  
Large Set ◽  
Functional Roles ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Structured Proteins ◽  
Disordered Regions

AbstractMany studies about classification and the functional annotation of intrinsically disordered proteins (IDPs) are based on either the occurrence of long disordered regions or the fraction of disordered residues in the sequence. Taking into account both criteria we separate the human proteome, taken as a case study, into three variants of proteins: i) ordered proteins (ORDPs), ii) structured proteins with intrinsically disordered regions (IDPRs), and iii) intrinsically disordered proteins (IDPs). The focus of this work is on the different functional roles of IDPs and IDPRs, which up until now have been generally considered as a whole. Previous studies assigned a large set of functional roles to the general category of IDPs. We show here that IDPs and IDPRs have non-overlapping functional spectra, play different roles in human diseases, and deserve to be treated as distinct categories of proteins. IDPs enrich only a few classes, functions, and processes: nucleic acid binding proteins, chromatin binding proteins, transcription factors, and developmental processes. In contrast, IDPRs are spread over several functional protein classes and GO annotations which they partly share with ORDPs. As regards to diseases, we observe that IDPs enrich only cancer-related proteins, at variance with previous results reporting that IDPs are widespread also in cardiovascular and neurodegenerative pathologies. Overall, the operational separation of IDPRs from IDPs is relevant towards correct estimates of the occurrence of intrinsically disordered proteins in genome-wide studies and in the understanding of the functional spectra associated to different flavors of protein disorder.

scholarly journals On the roles of intrinsically disordered proteins and regions in cell communication and signaling

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Sarah E. Bondos ◽  
A. Keith Dunker ◽  
Vladimir N. Uversky
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Cell Communication ◽  
Disordered Proteins ◽  
Sequence Structure ◽  
Intrinsically Disordered ◽  
Wide Range ◽  
Micro Organisms ◽  
Signaling Domains ◽  
Structured Proteins ◽  
Water Bears

AbstractFor proteins, the sequence → structure → function paradigm applies primarily to enzymes, transmembrane proteins, and signaling domains. This paradigm is not universal, but rather, in addition to structured proteins, intrinsically disordered proteins and regions (IDPs and IDRs) also carry out crucial biological functions. For these proteins, the sequence → IDP/IDR ensemble → function paradigm applies primarily to signaling and regulatory proteins and regions. Often, in order to carry out function, IDPs or IDRs cooperatively interact, either intra- or inter-molecularly, with structured proteins or other IDPs or intermolecularly with nucleic acids. In this IDP/IDR thematic collection published in Cell Communication and Signaling, thirteen articles are presented that describe IDP/IDR signaling molecules from a variety of organisms from humans to fruit flies and tardigrades (“water bears”) and that describe how these proteins and regions contribute to the function and regulation of cell signaling. Collectively, these papers exhibit the diverse roles of disorder in responding to a wide range of signals as to orchestrate an array of organismal processes. They also show that disorder contributes to signaling in a broad spectrum of species, ranging from micro-organisms to plants and animals.

scholarly journals The dynein light chain 8 (LC8) binds predominantly “in-register” to a multivalent intrinsically disordered partner

2020 ◽  
Vol 295 (15) ◽  
pp. 4912-4922 ◽  
Author(s):  
Patrick N. Reardon ◽  
Kayla A. Jara ◽  
Amber D. Rolland ◽  
Delaney A. Smith ◽  
Hanh T. M. Hoang ◽  
...  
Keyword(s):  
Light Chain ◽  
Intrinsically Disordered Proteins ◽  
Analytical Ultracentrifugation ◽  
Complex Dynamics ◽  
Regulatory Protein ◽  
Disordered Proteins ◽  
Dynein Light Chain ◽  
Linker Length ◽  
Intrinsically Disordered ◽  
Wide Range

Dynein light chain 8 (LC8) interacts with intrinsically disordered proteins (IDPs) and influences a wide range of biological processes. It is becoming apparent that among the numerous IDPs that interact with LC8, many contain multiple LC8-binding sites. Although it is established that LC8 forms parallel IDP duplexes with some partners, such as nucleoporin Nup159 and dynein intermediate chain, the molecular details of these interactions and LC8's interactions with other diverse partners remain largely uncharacterized. LC8 dimers could bind in either a paired “in-register” or a heterogeneous off-register manner to any of the available sites on a multivalent partner. Here, using NMR chemical shift perturbation, analytical ultracentrifugation, and native electrospray ionization MS, we show that LC8 forms a predominantly in-register complex when bound to an IDP domain of the multivalent regulatory protein ASCIZ. Using saturation transfer difference NMR, we demonstrate that at substoichiometric LC8 concentrations, the IDP domain preferentially binds to one of the three LC8 recognition motifs. Further, the differential dynamic behavior for the three sites and the size of the fully bound complex confirmed an in-register complex. Dynamics measurements also revealed that coupling between sites depends on the linker length separating these sites. These results identify linker length and motif specificity as drivers of in-register binding in the multivalent LC8–IDP complex assembly and the degree of compositional and conformational heterogeneity as a promising emerging mechanism for tuning of binding and regulation.

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