The sequence–ensemble relationship in fuzzy protein complexes

2021 ◽  
Vol 118 (37) ◽  
pp. e2020562118
Author(s):  
San Hadži ◽  
Remy Loris ◽  
Jurij Lah
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Protein Complexes ◽  
Structural Characteristics ◽  
Nmr Relaxation ◽  
Structural Heterogeneity ◽  
Conformational Space ◽  
Disordered Proteins ◽  
Statistical Thermodynamic ◽  
Intrinsically Disordered ◽  
Two Parameters

Intrinsically disordered proteins (IDPs) interact with globular proteins through a variety of mechanisms, resulting in the structurally heterogeneous ensembles known as fuzzy complexes. While there exists a reasonable comprehension on how IDP sequence determines the unbound IDP ensemble, little is known about what shapes the structural characteristics of IDPs bound to their targets. Using a statistical thermodynamic model, we show that the target-bound ensembles are determined by a simple code that combines the IDP sequence and the distribution of IDP–target interaction hotspots. These two parameters define the conformational space of target-bound IDPs and rationalize the observed structural heterogeneity of fuzzy complexes. The presented model successfully reproduces the dynamical signatures of target-bound IDPs from the NMR relaxation experiments as well as the changes of interaction affinity and the IDP helicity induced by mutations. The model explains how the target-bound IDP ensemble adapts to mutations in order to achieve an optimal balance between conformational freedom and interaction energy. Taken together, the presented sequence–ensemble relationship of fuzzy complexes explains the different manifestations of IDP disorder in folding-upon-binding processes.

scholarly journals Intrinsically disordered proteins identified in the aggregate proteome serve as biomarkers of neurodegeneration

2021 ◽  
Author(s):  
Srinivas Ayyadevara ◽  
Akshatha Ganne ◽  
Meenakshisundaram Balasubramaniam ◽  
Robert J. Shmookler Reis
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Protein Complexes ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Physiological Processes ◽  
Protein Partners ◽  
And Function ◽  
Computational Analyses ◽  
Disordered Regions

AbstractA protein’s structure is determined by its amino acid sequence and post-translational modifications, and provides the basis for its physiological functions. Across all organisms, roughly a third of the proteome comprises proteins that contain highly unstructured or intrinsically disordered regions. Proteins comprising or containing extensive unstructured regions are referred to as intrinsically disordered proteins (IDPs). IDPs are believed to participate in complex physiological processes through refolding of IDP regions, dependent on their binding to a diverse array of potential protein partners. They thus play critical roles in the assembly and function of protein complexes. Recent advances in experimental and computational analyses predicted multiple interacting partners for the disordered regions of proteins, implying critical roles in signal transduction and regulation of biological processes. Numerous disordered proteins are sequestered into aggregates in neurodegenerative diseases such as Alzheimer’s disease (AD) where they are enriched even in serum, making them good candidates for serum biomarkers to enable early detection of AD.

Molecular simulations of protein disorderThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (2) ◽  
pp. 269-290 ◽  
Author(s):  
Sarah Rauscher ◽  
Régis Pomès
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Peer Review Process ◽  
Structural Heterogeneity ◽  
Disordered Proteins ◽  
Cellular Biology ◽  
Protein Disorder ◽  
Conformational Ensembles ◽  
Intrinsically Disordered ◽  
Simulation Techniques ◽  
Selection Of

Protein disorder is abundant in proteomes throughout all kingdoms of life and serves many biologically important roles. Disordered states of proteins are challenging to study experimentally due to their structural heterogeneity and tendency to aggregate. Computer simulations, which are not impeded by these properties, have recently emerged as a useful tool to characterize the conformational ensembles of intrinsically disordered proteins. In this review, we provide a survey of computational studies of protein disorder with an emphasis on the interdisciplinary nature of these studies. The application of simulation techniques to the study of disordered states is described in the context of experimental and bioinformatics approaches. Experimental data can be incorporated into simulations, and simulations can provide predictions for experiment. In this way, simulations have been integrated into the existing methodologies for the study of disordered state ensembles. We provide recent examples of simulations of disordered states from the literature and our own work. Throughout the review, we emphasize important predictions and biophysical understanding made possible through the use of simulations. This review is intended as both an overview and a guide for structural biologists and theoretical biophysicists seeking accurate, atomic-level descriptions of disordered state ensembles.

Triple resonance 15N NMR relaxation experiments for studies of intrinsically disordered proteins

2017 ◽  
Vol 69 (3) ◽  
pp. 133-146 ◽  
Author(s):  
Pavel Srb ◽  
Jiří Nováček ◽  
Pavel Kadeřávek ◽  
Alžbeta Rabatinová ◽  
Libor Krásný ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Nmr Relaxation ◽  
Disordered Proteins ◽  
15N Nmr ◽  
Triple Resonance ◽  
Intrinsically Disordered ◽  
15N Nmr Relaxation ◽  
Relaxation Experiments

scholarly journals Ion Mobility Mass Spectrometry Measures the Conformational Landscape of p27 and Its Domains and How This Is Modulated upon Interaction with Cdk2/cyclin A

2018 ◽  
Author(s):  
Rebecca Beveridge ◽  
Lukasz Migas ◽  
Richard Kriwacki ◽  
Perdita E. Barran
Keyword(s):  
Mass Spectrometry ◽  
Ion Mobility ◽  
Intrinsically Disordered Proteins ◽  
Dynamic Properties ◽  
Cyclin A ◽  
Structural Heterogeneity ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Trimeric Complex ◽  
Conformational Landscape

Intrinsically disordered proteins have been reported to undergo ‘disorder to order’ transitions upon binding to their partners in the cell. The extent of the ordering on binding and the lack of order prior to binding is difficult to visualize with classical structure determination methods. Binding of p27 to the Cdk2/cyclin A complex is accompanied by partial folding of p27 in the KID domain, with the retention of dynamic behaviour for function, particularly in the C-terminal half of the protein, positioning it as an exemplary system to probe conformational diversity. Here we employ native ion mobility with mass spectrometry (IM-MS) to measure the intrinsic dynamic properties of p27, both in isolation and within the trimeric complex with Cdk2/cyclin A. This stepwise approach reveals the conformational distributions of the constituent proteins and how they are restructured on complex formation; the trimeric Cdk2/cyclin A/p27-KID complex possesses significant structural heterogeneity cf. Cdk2/cyclin A. These findings support the formation of a fuzzy complex in which both the N and C termini of p27 interact with Cdk2/cyclin A in multiple closely associated states.

scholarly journals Single-embryo phosphoproteomics reveals the importance of intrinsic disorder in cell cycle dynamics

2021 ◽  
Author(s):  
Juan Manuel Valverde ◽  
Geronimo Dubra ◽  
Henk van den Toorn ◽  
Guido van Mierlo ◽  
Michiel Vermeulen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Intrinsically Disordered Proteins ◽  
Protein Complexes ◽  
Disordered Proteins ◽  
Cell Cycles ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Egg Extracts ◽  
Cell Cycle Dynamics

Switch-like cyclin-dependent kinase (CDK)-1 activation is thought to underlie the abruptness of mitotic onset, but how CDKs can simultaneously phosphorylate many diverse substrates is unknown, and direct evidence for such phosphorylation dynamics in vivo is lacking. Here, we analysed protein phosphorylation states in single Xenopus embryos throughout synchronous cell cycles. Over a thousand phosphosites were dynamic in vivo, and assignment of cell cycle phases using egg extracts revealed hundreds of S-phase phosphorylations. Targeted phosphoproteomics in single embryos showed switch-like mitotic phosphorylation of diverse protein complexes. The majority of cell cycle-regulated phosphosites occurred in CDK consensus motifs, and 72% located to intrinsically disordered regions. Dynamically phosphorylated proteins, and documented substrates of cell cycle kinases, are significantly more disordered than phosphoproteins in general. Furthermore, 30-50% are components of membraneless organelles. Our results suggest that phosphorylation of intrinsically disordered proteins by cell cycle kinases, particularly CDKs, allows switch-like mitotic cellular reorganisation.

scholarly journals Physical Background of the Disordered Nature of “Mutual Synergetic Folding” Proteins

2018 ◽  
Vol 19 (11) ◽  
pp. 3340 ◽  
Author(s):  
Csaba Magyar ◽  
Anikó Mentes ◽  
Erzsébet Fichó ◽  
Miklós Cserző ◽  
István Simon
Keyword(s):  
Contact Surface ◽  
Driving Force ◽  
Structural Variation ◽  
Intrinsically Disordered Proteins ◽  
Main Chain ◽  
Protein Complexes ◽  
3D Structure ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Physical Background

Intrinsically disordered proteins (IDPs) lack a well-defined 3D structure. Their disordered nature enables them to interact with several other proteins and to fulfil their vital biological roles, in most cases after coupled folding and binding. In this paper, we analyze IDPs involved in a new mechanism, mutual synergistic folding (MSF). These proteins define a new subset of IDPs. Recently we collected information on these complexes and created the Mutual Folding Induced by Binding (MFIB) database. These protein complexes exhibit considerable structural variation, and almost half of them are homodimers, but there is a significant amount of heterodimers and various kinds of oligomers. In order to understand the basic background of the disordered character of the monomers found in MSF complexes, the simplest part of the MFIB database, the homodimers are analyzed here. We conclude that MFIB homodimeric proteins have a larger solvent-accessible main-chain surface area on the contact surface of the subunits, when compared to globular homodimeric proteins. The main driving force of the dimerization is the mutual shielding of the water-accessible backbones and the formation of extra intermolecular interactions.

scholarly journals Probing Local Backbone Geometries in Intrinsically Disordered Proteins by Cross-Correlated NMR Relaxation

2013 ◽  
Vol 52 (17) ◽  
pp. 4604-4606 ◽  
Author(s):  
Jan Stanek ◽  
Saurabh Saxena ◽  
Leonhard Geist ◽  
Robert Konrat ◽  
Wiktor Koźmiński
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Nmr Relaxation ◽  
Disordered Proteins ◽  
Intrinsically Disordered
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