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Mechanism and rate constants of the Cdc42 GTPase binding with intrinsically disordered effectors.

Title: Mechanism and rate constants of the Cdc42 GTPase binding with intrinsically disordered effectors.
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Name(s): Pang, Xiaodong, author
Zhou, Huan-Xiang, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2016-05-01
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Intrinsically disordered proteins (IDPs) are often involved in signaling and regulatory functions, through binding to cellular targets. Many IDPs undergo disorder-to-order transitions upon binding. Both the binding mechanisms and the magnitudes of the binding rate constants can have functional importance. Previously we have found that the coupled binding and folding of any IDP generally follows a sequential mechanism that we term dock-and-coalesce, whereby one segment of the IDP first docks to its subsite on the target surface and the remaining segments subsequently coalesce around their respective subsites. Here we applied our TransComp method within the framework of the dock-and-coalesce mechanism to dissect the binding kinetics of two Rho-family GTPases, Cdc42 and TC10, with two intrinsically disordered effectors, WASP and Pak1. TransComp calculations identified the basic regions preceding the GTPase binding domains (GBDs) of the effectors as the docking segment. For Cdc42 binding with both WASP and Pak1, the calculated docking rate constants are close to the observed overall binding rate constants, suggesting that basic-region docking is the rate-limiting step and subsequent conformational coalescence of the GBDs on the Cdc42 surface is fast. The possibility that conformational coalescence of the WASP GBD on the TC10 surface is slow warrants further experimental investigation. The account for the differences in binding rate constants among the three GTPase-effector systems and mutational effects therein yields deep physical and mechanistic insight into the binding processes. Our approach may guide the selection of mutations that lead to redesigned binding pathways.
Identifier: FSU_pmch_26879470 (IID), 10.1002/prot.25018 (DOI), PMC4840055 (PMCID), 26879470 (RID), 26879470 (EID)
Keywords: Binding kinetics, Coupled binding and folding, Dock-and-coalesce mechanism, Intrinsically disordered proteins, Transient-complex theory
Grant Number: R01 GM058187, GM0585187
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840055.
Subject(s): Binding Sites
Intrinsically Disordered Proteins/chemistry
Intrinsically Disordered Proteins/metabolism
Kinetics
Models, Molecular
Protein Binding
Wiskott-Aldrich Syndrome Protein/chemistry
Wiskott-Aldrich Syndrome Protein/metabolism
cdc42 GTP-Binding Protein/chemistry
cdc42 GTP-Binding Protein/metabolism
p21-Activated Kinases/chemistry
p21-Activated Kinases/metabolism
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_26879470
Owner Institution: FSU
Is Part Of: Proteins.
1097-0134
Issue: iss. 5, vol. 84

Choose the citation style.
Pang, X., & Zhou, H. -X. (2016). Mechanism and rate constants of the Cdc42 GTPase binding with intrinsically disordered effectors. Proteins. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_26879470