Fuzziness enables context dependence of protein interactions

Miskei, Márton; Gregus, Andrea; Sharma, Rashmi; Duro, Norbert; Zsolyomi, Fruzsina; Fuxreiter, Mónika

doi:10.1002/1873-3468.12762

Cited by 65 publications

(53 citation statements)

References 81 publications

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“…The presence of fuzzy interacting regions adjacent to the main binding elements can regulate binding affinity, specificity, and selectivity . Fuzzy regions also facilitate IDPs/IDRs‐mediated allosteric communication . Furthermore, transient binding interactions can promote formation of non‐native interactions stabilizing the encounter complexes, thus enhance the binding kinetics .…”

Section: Dynamic Contacts and Fuzzy Interactionsmentioning

confidence: 99%

“…[180][181][182][183] Fuzzy regions also facilitate IDPs/IDRs-mediated allosteric communication. 184 Furthermore, transient binding interactions can promote formation of non-native interactions stabilizing the encounter complexes, thus enhance the binding kinetics. 185 Dynamic interactions can also modulate the foldingbinding mechanism of IDPs/IDRs.…”

Section: Dynamic Contacts and Fuzzy Interactionsmentioning

confidence: 99%

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Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

et al. 2019

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The sequence–structure–function paradigm of proteins has been revolutionized by the discovery of intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). In contrast to traditional ordered proteins, IDPs/IDRs are unstructured under physiological conditions. The absence of well‐defined three‐dimensional structures in the free state of IDPs/IDRs is fundamental to their function. Folding upon binding is an important mode of molecular recognition for IDPs/IDRs. While great efforts have been devoted to investigating the complex structures and binding kinetics and affinities, our knowledge on the binding mechanisms of IDPs/IDRs remains very limited. Here, we review recent advances on the binding mechanisms of IDPs/IDRs. The structures and kinetic parameters of IDPs/IDRs can vary greatly, and the binding mechanisms can be highly dependent on the structural properties of IDPs/IDRs. IDPs/IDRs can employ various combinations of conformational selection and induced fit in a binding process, which can be templated by the target and/or encoded by the IDP/IDR. Further studies should provide deeper insights into the molecular recognition of IDPs/IDRs and enable the rational design of IDP/IDR binding mechanisms in the future.

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Section: Dynamic Contacts and Fuzzy Interactionsmentioning

confidence: 99%

Section: Dynamic Contacts and Fuzzy Interactionsmentioning

confidence: 99%

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

et al. 2019

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“…Table S1 lists the refinement statistics. The asymmetric unit of the interacts with the phosphorylated carboxyl-terminus GPCRs (referred to as receptor tail) first, 25 which displaces the carboxyl-terminal tail of βarr2 docked in the N-domain. Afterwards, βarr2 engages with the intracellular surface of the seven transmembrane bundle (referred to as receptor core) though multiple loops.…”

Section: Methodsmentioning

confidence: 99%

“…2). Given that the N-domain of βarr2 should interact with hundreds of different patterns of the GPCR Rp-tail, the complex between them might be modular, which has often been observed in disordered proteins 25,26 . The large dependence of electrostatic interactions between βarr2 and Rp-tails might enable βarr2 to pair promiscuously with hundreds of GPCRs containing differently phosphorylated Rp-tails.…”

Section: Distinct Binding Modes Of C7pp1 Compared To Other Rp-tailsmentioning

confidence: 99%

Crystal structure of β-arrestin 2 in complex with an atypical chemokine receptor phosphopeptide reveals an alternative active conformation

Min

Yoon

Park

et al. 2019

Preprint

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β-arrestins (βarrs) critically regulate signaling and trafficking of G protein-coupled receptors (GPCRs), the largest family of drug targets in the human genome, and there are two isoforms of βarrs: βarr1 and βarr2. Most GPCRs interact with both the heterotrimeric G-proteins and βarrs, inducing distinct downstream signal transduction. However, certain chemokine receptors lack functional G-protein coupling, but they can efficiently recruit βarrs upon agonist-stimulation, and they are referred to as atypical chemokine receptors (ACKRs). Receptor phosphorylation is a key determinant for the binding of βarrs, and understanding the intricate details of receptor-βarr interaction is the next frontier in GPCR structural biology. To date, the high-resolution structures of active βarr1 have been revealed, but the activation mechanism of βarr2 by a phosphorylated GPCR remains elusive. Here, we present a 1.95 Å crystal structure of βarr2 in complex with a phosphopeptide (C7pp) derived from the carboxyl-terminus of ACKR3, also known as CXCR7.The structure of C7pp-bound βarr2 reveals key differences from the previously determined active conformation of βarr1. One of the key differences is that C7pp-bound βarr2 shows a relatively small inter-domain rotation. An antibody-fragment-based conformational sensor and hydrogen/deuterium exchange experiments further corroborate structural features and suggest that the determined structure is an alternative active conformation of βarr2.

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“…In addition, the Review by Jores and Rapaport examines the early steps that determine proper localization of β‐barrel proteins at the outer mitochondrial membrane. Finally, Miskei and colleagues report on how intrinsic disorder is a prerequisite for proteins to undergo structural dynamic transitions in order to accommodate to their cellular requirements.…”

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confidence: 99%

Jerusalem Special Issue

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2017

FEBS Letters

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This year the FEBS Congress is taking place in Jerusalem, an emblematic historical city where different religions and civilizations meet. Throughout the centuries, Jerusalem has hosted numerous leading figures in many areas of arts and sciences. The names and activities of several Nobel laureates are associated with this city and the Hebrew University of Jerusalem. The renowned physicist Albert Einstein was one of the founders of this University, and was highly engaged in its development. Today the Hebrew University of Jerusalem hosts more than 2000 papers and personal belongings of Einstein's in the Einstein Archives, a recommended destination to everyone visiting Jerusalem.The FEBS Congress will present nearly the entire spectrum of molecular life sciences in more than 20 symposia. The present Special Issue features Review articles reflecting this wide range of topics and provides the reader with a broad overview of what will be discussed at the Congress.The first two articles both relate to cellular 3D structures. Goodstadt and Marti-Renom discuss the complexity of 3D representations of genomes and the challenges related to the visualization of novel spatial data [1]. A completely different way to approach 3D views is cryo-electron tomography. Wagner and colleagues review recent technological developments, such as Volta phase plate or cryo-focused ion beam milling, that have emerged for visualizing high-resolution cellular structures and allow for structural studies in unprecedented detail [2].Stress granules represent a particular aspect of mRNA localization. The location and timing of their formation, as well as the mechanisms through which mRNA-protein complexes accumulate and interact with stress granules are discussed by .A number of Review articles focus on various signaling processes, such as Death Receptor 3 signaling and its function in the immune system (Bittner and Ehrenschwender) [4]; the structure-function relationship of ion channel transporters and their role in cell signaling (Abbott) [5]; new approaches to identify regulatory kinases by phospho-proteomics (Dermit et al.) [6]; the mammalian central satiety pathway involving hypothalamic neurons in the arcuate nucleus (Rubinstein and Low) [7]; and a searchable database of ERK target proteins based on phospho-proteomic technology ( € Unal et al.) [8]. A further set of Review articles covers protein degradation and homeostasis. A major well-known degradation pathway is the ubiquitin/proteasome system in which numerous E3 ubiquitin ligases collaborate with molecular chaperones to recognize and degrade their substrates and, in case of malfunctioning, give rise to pathological conditions (Kevei et al.) [9]. A detailed Review on HECT E3 ligases addresses how the catalytic activity of Nedd4 family members is regulated (Fajner et al.) [10]. The role of the molecular chaperone Hsp70 in protein substrate degradation is shown to involve a combination of interacting partners, co-chaperones, and other chaperones (Fernandez-Fernandez et al.) [11].Oxidative...

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Fuzziness enables context dependence of protein interactions

Cited by 65 publications

References 81 publications

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

Crystal structure of β-arrestin 2 in complex with an atypical chemokine receptor phosphopeptide reveals an alternative active conformation

Jerusalem Special Issue

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