Topological frustration leading to backtracking in a coupled folding-binding process

2021 ◽  
Author(s):  
Meng Gao ◽  
Ping Li ◽  
Zhengding Su ◽  
Yongqi Huang
Keyword(s):  
Structure Function ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Biological Processes ◽  
Sequence Structure ◽  
Binding Process ◽  
Intrinsically Disordered

Intrinsically disordered proteins (IDPs) are abundant in all species. Their discovery challenges the traditional “sequence−structure−function” paradigm of protein science, because IDPs play important roles in various biological processes without preformed...

scholarly journals Interplay between folding and binding modulates protein sequences, structures, functions and regulation

2017 ◽  
Author(s):  
Bálint Mészáros ◽  
László Dobson ◽  
Erzsébet Fichó ◽  
Gábor E. Tusnády ◽  
Zsuzsanna Dosztányi ◽  
...  
Keyword(s):  
Structural Properties ◽  
Regulatory Networks ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Binding Modes ◽  
Sequence Structure ◽  
Binding Partner ◽  
Binding Process ◽  
Intrinsically Disordered ◽  
Protein Interactome

SummaryIntrinsically Disordered Proteins (IDPs) fulfill critical biological roles without having the potential to fold on their own. While lacking inherent structure, the majority of IDPs do reach a folded state via interaction with a protein partner, presenting a deep entanglement of the folding and binding process. Protein disorder has been recognized as a major determinant in several properties of proteins; yet the way the binding process is reflected in these features in general lacks this detail of description. Recent advances in database development enabled us to identify three basic scenarios of the interplay between folding and binding in unprecedented detail. These scenarios have fundamentally different properties in terms of protein sequence, structure, function and regulation, depending on the structural properties of the interacting partners. Strikingly, the existence of a binding partner and its structural properties influence all analyzed properties of proteins to the same extent as the divide between inherent order or disorder. The appreciation of this interplay between folding and binding is the basis for the successful charting of unknown territories in the protein interactome, the understanding of how different binding modes assemble regulatory networks, and the development of future pharmaceutical applications.

scholarly journals Intrinsically Disordered Proteins as Regulators of Transient Biological Processes and as Untapped Drug Targets

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2118
Author(s):  
Yusuke Hosoya ◽  
Junko Ohkanda
Keyword(s):  
Drug Targets ◽  
Intrinsically Disordered Proteins ◽  
Dynamic Control ◽  
Disordered Proteins ◽  
Biological Processes ◽  
Phase Separations ◽  
Cellular Processes ◽  
Intrinsically Disordered ◽  
New Drug ◽  
Liquid Phase Separations

Intrinsically disordered proteins (IDPs) are critical players in the dynamic control of diverse cellular processes, and provide potential new drug targets because their dysregulation is closely related to many diseases. This review focuses on several medicinal studies that have identified low-molecular-weight inhibitors of IDPs. In addition, clinically relevant liquid–liquid phase separations—which critically involve both intermolecular interactions between IDPs and their posttranslational modification—are analyzed to understand the potential of IDPs as new drug targets.

scholarly journals The mechanism of coupled folding-upon-binding of an intrinsically disordered protein

2020 ◽  
Author(s):  
Paul Robustelli ◽  
Stefano Piana ◽  
David E. Shaw
Keyword(s):  
Measles Virus ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Disordered Proteins ◽  
Binding Process ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Induced Folding ◽  
Helical Content ◽  
Intermolecular Contacts

AbstractIntrinsically disordered proteins (IDPs), which in isolation do not adopt a well-defined tertiary structure but instead populate a structurally heterogeneous ensemble of interconverting states, play important roles in many biological pathways. IDPs often fold into ordered states upon binding to their physiological interaction partners (a so-called “folding-upon-binding” process), but it has proven difficult to obtain an atomic-level description of the structural mechanisms by which they do so. Here, we describe in atomic detail the folding-upon-binding mechanism of an IDP segment to its binding partner, as observed in unbiased molecular dynamics simulations. In our simulations, we observed over 70 binding and unbinding events between the α-helical molecular recognition element (α-MoRE) of the intrinsically disordered C-terminal domain of the measles virus nucleoprotein (NTAIL) and the X domain (XD) of the measles virus phosphoprotein complex. We found that folding-upon-binding primarily occurred through induced-folding pathways (in which intermolecular contacts form before or concurrently with the secondary structure of the disordered protein)—an observation supported by previous experiments—and that the transition state ensemble was characterized by the formation of just a few key intermolecular contacts, and was otherwise highly structurally heterogeneous. We found that when a large amount of helical content was present early in a transition path, NTAIL typically unfolded, then refolded after additional intermolecular contacts formed. We also found that, among conformations with similar numbers of intermolecular contacts, those with less helical content had a higher probability of ultimately forming the native complex than conformations with more helical content, which were more likely to unbind. These observations suggest that even after intermolecular contacts have formed, disordered regions can have a kinetic advantage over folded regions in the folding-upon-binding process.

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 Common Functions of Disordered Proteins across Evolutionary Distant Organisms

2020 ◽  
Vol 21 (6) ◽  
pp. 2105 ◽  
Author(s):  
Arndt Wallmann ◽  
Christopher Kesten
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Plant Proteins ◽  
Sequence Structure ◽  
Intrinsically Disordered ◽  
Bioinformatic Approaches ◽  
The Common ◽  
Function Relationship

Intrinsically disordered proteins and regions typically lack a well-defined structure and thus fall outside the scope of the classic sequence–structure–function relationship. Hence, classic sequence- or structure-based bioinformatic approaches are often not well suited to identify homology or predict the function of unknown intrinsically disordered proteins. Here, we give selected examples of intrinsic disorder in plant proteins and present how protein function is shared, altered or distinct in evolutionary distant organisms. Furthermore, we explore how examining the specific role of disorder across different phyla can provide a better understanding of the common features that protein disorder contributes to the respective biological mechanism.

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