Distinct mechanisms of a phosphotyrosyl peptide binding to two SH2 domains

Pang, Xiaodong; Zhou, Huan‐Xiang

doi:10.1142/s0219633614400033

Cited by 4 publications

(8 citation statements)

References 37 publications

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“…The docking rate constants can be significantly enhanced by long-range electrostatic attraction, as found here as well as for a number of other IDPs [6, 12, 20, 22, 31, 32], reminiscent of the situation for the association rate constants of structured proteins [26, 28–30]. On the other hand, the coalescing rate constants are dictated by the free energy barriers, which in turn are determined by secondary structure propensities of the coalescing segments [11, 14] and their short-range intermolecular interactions with the target surface [13, 19].…”

Section: Discussionsupporting

confidence: 66%

“…By applying the TransComp method to different segments of an IDP, we can identify the docking segment of the dominant pathway and predict the rate constant of the docking step, thereby providing an upper bound for the rate constant of the overall binding process. This approach has yielded rate constants in good agreement with experimental results for a number of IDPs [4,26,27,31,32]. The 502-residue WASP comprises a WASP-homology-1 (WH1) domain, the GBD (residues 225-310) containing a basic region (BR; residues 225-237) and a Cdc42/Rac1-interactive binding (CRIB) motif (residues 238-251), and a VCA domain ( Fig.…”

Section: Docksupporting

confidence: 67%

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The dock‐and‐coalesce mechanism for the association of a WASP disordered region with the Cdc42 GTPase

Matthews

Pang

et al. 2017

The FEBS Journal

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Intrinsically disordered proteins (IDPs) play key roles in signaling and regulation. Many IDPs undergo folding upon binding to their targets. We have proposed that coupled folding and binding of IDPs generally follow a dock-and-coalesce mechanism, whereby a segment of the IDP, through diffusion, docks to its cognate subsite and, subsequently, the remaining segments coalesce around their subsites. Here, by a combination of experiment and computation, we determined the precise form of dock-and-coalesce operating in the association between the intrinsically disordered GTPase binding domain (GBD) of the Wiskott-Aldrich Syndrome protein (WASP) and the Cdc42 GTPase. The association rate constants (ka) were measured by stopped-flow fluorescence under various solvent conditions. ka reached 107 M−1s−1 at physiological ionic strength and had a strong salt dependence, suggesting that an electrostatically enhanced, diffusion-controlled docking step may be rate-limiting. Our computation, based on the transient-complex theory, identified the N-terminal basic region of the GBD as the docking segment. However, several other changes in solvent conditions provided strong evidence that the coalescing step also contributed to determining the magnitude of ka. Addition of glucose and trifluoroethanol and an increase in temperature all produced experimental ka values much higher than expected from the effects on the docking rate alone. Conversely, addition of urea led to ka values much lower than expected if only the docking rate was affected. These results all pointed to ka being approximately two thirds of the docking rate constant under physiological solvent conditions.

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Section: Discussionsupporting

confidence: 66%

Section: Docksupporting

confidence: 67%

The dock‐and‐coalesce mechanism for the association of a WASP disordered region with the Cdc42 GTPase

Matthews

Pang

et al. 2017

The FEBS Journal

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“…For a phosphopeptide binding to two different SH2 domains, while the rate constants are electrostatically enhanced in both cases, as shown by decreased rates with increasing extents of dephosphorylation, 582,583 the binding mechanisms were different, one forming the native complex all at once while the other involving dock-and-coalesce. 584 Interestingly, for the binding of the disordered Wiskott–Aldrich syndrome protein (WASP) to the Cdc42 GTPase (Figure 18), when the docking step with one segment was slowed down substantially by charge mutations, docking with another segment came into play, so that multiple dock-and- coalesce pathways started to contribute to the overall binding process. 575 Significant electrostatic rate enhancement has also been observed in the binding of other IDPs, again implicating a diffusion-limited docking step playing a major rate-determining role.…”

Section: Kinetics Of Protein Folding and Bindingmentioning

confidence: 99%

Electrostatic Interactions in Protein Structure, Folding, Binding, and Condensation

2018

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Charged and polar groups, through forming ion pairs, hydrogen bonds, and other less specific electrostatic interactions, impart important properties to proteins. Modulation of the charges on the amino acids, e.g., by pH and by phosphorylation and dephosphorylation, have significant effects such as protein denaturation and switch-like response of signal transduction networks. This review aims to present a unifying theme among the various effects of protein charges and polar groups. Simple models will be used to illustrate basic ideas about electrostatic interactions in proteins, and these ideas in turn will be used to elucidate the roles of electrostatic interactions in protein structure, folding, binding, condensation, and related biological functions. In particular, we will examine how charged side chains are spatially distributed in various types of proteins and how electrostatic interactions affect thermodynamic and kinetic properties of proteins. Our hope is to capture both important historical developments and recent experimental and theoretical advances in quantifying electrostatic contributions of proteins.

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“…Based on the transient complex theory, the TransComp method has been successfully applied to reproduce and predict the binding rates for various protein‐protein complexes and has recently been applied to study the binding mechanisms for IDPs . In this work, by applying the TransComp method, we investigated the binding kinetics for the KIX domain with several intrinsically disordered transcription factors.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the transient complex theory, Zhou et al developed the TransComp method to predict the association rates for protein–protein interactions and understand the binding mechanisms of IDPs . According to the transient complex theory, the association rate constant for a diffusion‐limited binding process is expressed as k a = k a0 exp(−Δ G el */ k B T ), where k a0 is the basal rate constant for forming the transient complex via random diffusion, and Δ G el * is the electrostatic interaction energy of the transient complex .…”

Section: Methodsmentioning

confidence: 99%

Deciphering the promiscuous interactions between intrinsically disordered transactivation domains and the KIX domain

et al. 2017

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The kinase-inducible domain interacting (KIX) domain of the transcriptional coactivator CBP protein carries 2 isolated binding sites (designated as the c-Myb site and the MLL site) and is capable of binding numerous intrinsically disordered transactivation domains (TADs), including c-Myb and pKID via the c-Myb site, and MLL, E2A and c-Jun via the MLL site. In this study we compared the kinetics for binding of various disordered TADs to the KIX domain via computational biophysical analyses. We found that the binding rates are heavily affected by long-range electrostatic interactions. The basal rate constants for forming the encounter complexes are similar for different KIX binding peptides, favorable electrostatic interactions between the MLL site and the peptides result in greater association rates when peptides bind to the MLL site. FOXO3a and p53 TAD each contains 2 copies of KIX binding motif and each motif interacts with both the MLL site and the c-Myb site. Our kinetics studies suggest that binding of FOXO3a or p53 TAD to the KIX domain is via a sequential mechanism, where one KIX binding motif binds to the MLL site first and then the other KIX binding motif binds to the c-Myb site. Considering the promiscuous interactions between FOXO3a and KIX, and p53 TAD and KIX, electrostatic steering simplifies the binding mechanism. This study highlights the importance of long-range electrostatic interactions in molecular recognition process involving multi-motif intrinsically disordered proteins and promiscuous interactions.

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Distinct mechanisms of a phosphotyrosyl peptide binding to two SH2 domains

Cited by 4 publications

References 37 publications

The dock‐and‐coalesce mechanism for the association of a WASP disordered region with the Cdc42 GTPase

The dock‐and‐coalesce mechanism for the association of a WASP disordered region with the Cdc42 GTPase

Electrostatic Interactions in Protein Structure, Folding, Binding, and Condensation

Deciphering the promiscuous interactions between intrinsically disordered transactivation domains and the KIX domain

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