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dock-and-coalesce mechanism for the association of a WASP disordered region with the Cdc42 GTPase.

Title: The dock-and-coalesce mechanism for the association of a WASP disordered region with the Cdc42 GTPase.
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Name(s): Ou, Li, author
Matthews, Megan, author
Pang, Xiaodong, author
Zhou, Huan-Xiang, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2017-10-01
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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 and the Cdc42 GTPase. The association rate constants (k ) were measured by stopped-flow fluorescence under various solvent conditions. k reached 10 m ·s 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 k . Addition of glucose and trifluoroethanol and an increase in temperature all produced experimental k values much higher than expected from the effects on the docking rate alone. Conversely, addition of urea led to k values much lower than expected if only the docking rate was affected. These results all pointed to k being approximately two-thirds of the docking rate constant under physiological solvent conditions.
Identifier: FSU_pmch_28805312 (IID), 10.1111/febs.14197 (DOI), PMC5643242 (PMCID), 28805312 (RID), 28805312 (EID)
Keywords: Association rate, Dock-and-coalesce, Folding upon binding, Intrinsically disordered proteins, Transient-complex theory
Grant Number: R01 GM058187, R35 GM118091
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643242.
Subject(s): Humans
Intrinsically Disordered Proteins/chemistry
Intrinsically Disordered Proteins/metabolism
Protein Binding
Wiskott-Aldrich Syndrome Protein/chemistry
Wiskott-Aldrich Syndrome Protein/metabolism
cdc42 GTP-Binding Protein/chemistry
cdc42 GTP-Binding Protein/metabolism
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_28805312
Owner Institution: FSU
Is Part Of: The FEBS journal.
1742-4658
Issue: iss. 20, vol. 284

Choose the citation style.
Ou, L., Matthews, M., Pang, X., & Zhou, H. -X. (2017). The dock-and-coalesce mechanism for the association of a WASP disordered region with the Cdc42 GTPase. The Febs Journal. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_28805312