The Dynamic Multisite Interactions between Two Intrinsically Disordered Proteins

Wu, Shaowen; Wang, Dongdong; Liu, Jin; Feng, Yitao; Weng, Jingwei; Liu, Yu; Gao, Xin; Liu, Jianwei; Wang, Wenning

doi:10.1002/anie.201701883

Cited by 46 publications

(76 citation statements)

References 28 publications

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“…The first clearly characterized extremely fuzzy complex is 4.1G-CTD/NuMA [38]. Protein 4.1 is a ubiquitously expressed adaptor protein, which serves as a hub organizing signaling complexes involving many membrane proteins [40].…”

Section: Interaction Between 41g-ctd and Numamentioning

confidence: 99%

“…Therefore, whether two IDPs can interact directly to form a fuzzy complex while retaining structural plasticity remains an open question [37]. Recently, this question has been answered by two studies [38,39] with detailed characterizations of the interactions between two pairs of IDPs that form dynamic fuzzy complexes. In both cases, the structural disorder and conformational dynamics of the two interacting IDPs are preserved in the complexes.…”

Section: Introductionmentioning

confidence: 99%

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Extreme Fuzziness: Direct Interactions between Two IDPs

Wang

2019

Biomolecules

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Protein interactions involving intrinsically disordered proteins (IDPs) greatly extend the range of binding mechanisms available to proteins. In interactions employing coupled folding and binding, IDPs undergo disorder-to-order transitions to form a complex with a well-defined structure. In many other cases, IDPs retain structural plasticity in the final complexes, which have been defined as the fuzzy complexes. While a large number of fuzzy complexes have been characterized with variety of fuzzy patterns, many of the interactions are between an IDP and a structured protein. Thus, whether two IDPs can interact directly to form a fuzzy complex without disorder-to-order transition remains an open question. Recently, two studies of interactions between IDPs (4.1G-CTD/NuMA and H1/ProTα) have found a definite answer to this question. Detailed characterizations combined with nuclear magnetic resonance (NMR), single-molecule Förster resonance energy transfer (smFRET) and molecular dynamics (MD) simulation demonstrate that direct interactions between these two pairs of IDPs do form fuzzy complexes while retaining the conformational dynamics of the isolated proteins, which we name as the extremely fuzzy complexes. Extreme fuzziness completes the full spectrum of protein-protein interaction modes, suggesting that a more generalized model beyond existing binding mechanisms is required. Previous models of protein interaction could be applicable to some aspects of the extremely fuzzy interactions, but in more general sense, the distinction between native and nonnative contacts, which was used to understand protein folding and binding, becomes obscure. Exploring the phenomenon of extreme fuzziness may shed new light on molecular recognition and drug design.

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Section: Interaction Between 41g-ctd and Numamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Extreme Fuzziness: Direct Interactions between Two IDPs

Wang

2019

Biomolecules

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“…Similar stochastic transitions between FRET efficiency levels were observed in the smFRET traces for protein 4.1, a cytoskeletal adaptor protein that stabilizes spectrin–actin crosslinks [32]. The protein appeared to switch between an unresolved number of discrete conformational states.…”

Section: Evidence Of Configuration Switching In Idp Studiesmentioning

confidence: 55%

Spontaneous Switching among Conformational Ensembles in Intrinsically Disordered Proteins

et al. 2019

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The common conception of intrinsically disordered proteins (IDPs) is that they stochastically sample all possible configurations driven by thermal fluctuations. This is certainly true for many IDPs, which behave as swollen random coils that can be described using polymer models developed for homopolymers. However, the variability in interaction energy between different amino acid sequences provides the possibility that some configurations may be strongly preferred while others are forbidden. In compact globular IDPs, core hydration and packing density can vary between segments of the polypeptide chain leading to complex conformational dynamics. Here, we describe a growing number of proteins that appear intrinsically disordered by biochemical and bioinformatic characterization but switch between restricted regions of conformational space. In some cases, spontaneous switching between conformational ensembles was directly observed, but few methods can identify when an IDP is acting as a restricted chain. Such switching between disparate corners of conformational space could bias ligand binding and regulate the volume of IDPs acting as structural or entropic elements. Thus, mapping the accessible energy landscape and capturing dynamics across a wide range of timescales are essential to recognize when an IDP is acting as such a switch.

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“…Cytoplasmic regions of disordered domains of several neuronal proteins including neuroligin and C-terminal domain of N -methyl- d -aspartic Acid (NMDA) receptor subunit GluN2B (abbreviated C-term-N2B from here on) were observed to give smFRET signals that indicated spontaneous switching among well separated FRET states that persisted for lifetimes of a few seconds, while other measures of the proteins indicated no formation of folded structures [71]. Similar behavior has been detected by smFRET for the disordered protein 4.1-G, which is an adaptor protein linking the cytoskeleton to membrane proteins [73].…”

Section: Unique Phenomena Identified By Applying Single Molecule Fmentioning

confidence: 78%

Single Molecule FRET: A Powerful Tool to Study Intrinsically Disordered Proteins

2018

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Intrinsically disordered proteins (IDPs) are often modeled using ideas from polymer physics that suggest they smoothly explore all corners of configuration space. Experimental verification of this random, dynamic behavior is difficult as random fluctuations of IDPs cannot be synchronized across an ensemble. Single molecule fluorescence (or Förster) resonance energy transfer (smFRET) is one of the few approaches that are sensitive to transient populations of sub-states within molecular ensembles. In some implementations, smFRET has sufficient time resolution to resolve transitions in IDP behaviors. Here we present experimental issues to consider when applying smFRET to study IDP configuration. We illustrate the power of applying smFRET to IDPs by discussing two cases in the literature of protein systems for which smFRET has successfully reported phosphorylation-induced modification (but not elimination) of the disordered properties that have been connected to impacts on the related biological function. The examples we discuss, PAGE4 and a disordered segment of the GluN2B subunit of the NMDA receptor, illustrate the great potential of smFRET to inform how IDP function can be regulated by controlling the detailed ensemble of disordered states within biological networks.

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The Dynamic Multisite Interactions between Two Intrinsically Disordered Proteins

Cited by 46 publications

References 28 publications

Extreme Fuzziness: Direct Interactions between Two IDPs

Extreme Fuzziness: Direct Interactions between Two IDPs

Spontaneous Switching among Conformational Ensembles in Intrinsically Disordered Proteins

Single Molecule FRET: A Powerful Tool to Study Intrinsically Disordered Proteins

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