The nucleotide switch in Cdc42 modulates coupling between the GTPase-binding and allosteric equilibria of Wiskott-Aldrich syndrome protein

Daisy W. Leung, Michael K. Rosen

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The GTP/GDP nucleotide switch in Ras superfamily GTPases generally involves differential affinity toward downstream effectors, with the GTP-bound state having a higher affinity for effector than the GDP-bound state. We have developed a quantitative model of allosteric regulation of the Wiskott-Aldrich syndrome protein (WASP) by the Rho GTPase Cdc42 to better understand how GTPase binding is coupled to effector activation. The model accurately predicts WASP affinity for Cdc42, activity toward Arp2/3 complex, and activation by Cdc42 as functions of a two-state allosteric equilibrium in WASP. The ratio of GTPase affinities for the inactive and active states of WASP is appreciably larger for Cdc42-GTP than for Cdc42-GDP. The greater ability to distinguish between the two states of WASP makes Cdc42-GTP a full WASP agonist, whereas Cdc42-GDP is only a partial agonist. Thus, the nucleotide switch controls not only the affinity of Cdc42 for its effector but also the efficiency of coupling between the Cdc42-binding and allosteric equilibria in WASP. This effect can ensure high fidelity and specificity in Cdc42 signaling in crowded membrane environments.

Original languageEnglish (US)
Pages (from-to)5685-5690
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number16
DOIs
StatePublished - Apr 19 2005

Fingerprint

Wiskott-Aldrich Syndrome Protein
GTP Phosphohydrolases
Nucleotides
Guanosine Triphosphate
Actin-Related Protein 2-3 Complex
Allosteric Regulation
ras Proteins
rho GTP-Binding Proteins
Membranes

Keywords

  • Allostery
  • Signal transduction

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

@article{1b189a93a0314ab4a4e48c00bb2f0a68,
title = "The nucleotide switch in Cdc42 modulates coupling between the GTPase-binding and allosteric equilibria of Wiskott-Aldrich syndrome protein",
abstract = "The GTP/GDP nucleotide switch in Ras superfamily GTPases generally involves differential affinity toward downstream effectors, with the GTP-bound state having a higher affinity for effector than the GDP-bound state. We have developed a quantitative model of allosteric regulation of the Wiskott-Aldrich syndrome protein (WASP) by the Rho GTPase Cdc42 to better understand how GTPase binding is coupled to effector activation. The model accurately predicts WASP affinity for Cdc42, activity toward Arp2/3 complex, and activation by Cdc42 as functions of a two-state allosteric equilibrium in WASP. The ratio of GTPase affinities for the inactive and active states of WASP is appreciably larger for Cdc42-GTP than for Cdc42-GDP. The greater ability to distinguish between the two states of WASP makes Cdc42-GTP a full WASP agonist, whereas Cdc42-GDP is only a partial agonist. Thus, the nucleotide switch controls not only the affinity of Cdc42 for its effector but also the efficiency of coupling between the Cdc42-binding and allosteric equilibria in WASP. This effect can ensure high fidelity and specificity in Cdc42 signaling in crowded membrane environments.",
keywords = "Allostery, Signal transduction",
author = "Leung, {Daisy W.} and Rosen, {Michael K.}",
year = "2005",
month = "4",
day = "19",
doi = "10.1073/pnas.0406472102",
language = "English (US)",
volume = "102",
pages = "5685--5690",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "16",

}

TY - JOUR

T1 - The nucleotide switch in Cdc42 modulates coupling between the GTPase-binding and allosteric equilibria of Wiskott-Aldrich syndrome protein

AU - Leung, Daisy W.

AU - Rosen, Michael K.

PY - 2005/4/19

Y1 - 2005/4/19

N2 - The GTP/GDP nucleotide switch in Ras superfamily GTPases generally involves differential affinity toward downstream effectors, with the GTP-bound state having a higher affinity for effector than the GDP-bound state. We have developed a quantitative model of allosteric regulation of the Wiskott-Aldrich syndrome protein (WASP) by the Rho GTPase Cdc42 to better understand how GTPase binding is coupled to effector activation. The model accurately predicts WASP affinity for Cdc42, activity toward Arp2/3 complex, and activation by Cdc42 as functions of a two-state allosteric equilibrium in WASP. The ratio of GTPase affinities for the inactive and active states of WASP is appreciably larger for Cdc42-GTP than for Cdc42-GDP. The greater ability to distinguish between the two states of WASP makes Cdc42-GTP a full WASP agonist, whereas Cdc42-GDP is only a partial agonist. Thus, the nucleotide switch controls not only the affinity of Cdc42 for its effector but also the efficiency of coupling between the Cdc42-binding and allosteric equilibria in WASP. This effect can ensure high fidelity and specificity in Cdc42 signaling in crowded membrane environments.

AB - The GTP/GDP nucleotide switch in Ras superfamily GTPases generally involves differential affinity toward downstream effectors, with the GTP-bound state having a higher affinity for effector than the GDP-bound state. We have developed a quantitative model of allosteric regulation of the Wiskott-Aldrich syndrome protein (WASP) by the Rho GTPase Cdc42 to better understand how GTPase binding is coupled to effector activation. The model accurately predicts WASP affinity for Cdc42, activity toward Arp2/3 complex, and activation by Cdc42 as functions of a two-state allosteric equilibrium in WASP. The ratio of GTPase affinities for the inactive and active states of WASP is appreciably larger for Cdc42-GTP than for Cdc42-GDP. The greater ability to distinguish between the two states of WASP makes Cdc42-GTP a full WASP agonist, whereas Cdc42-GDP is only a partial agonist. Thus, the nucleotide switch controls not only the affinity of Cdc42 for its effector but also the efficiency of coupling between the Cdc42-binding and allosteric equilibria in WASP. This effect can ensure high fidelity and specificity in Cdc42 signaling in crowded membrane environments.

KW - Allostery

KW - Signal transduction

UR - http://www.scopus.com/inward/record.url?scp=17644377914&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=17644377914&partnerID=8YFLogxK

U2 - 10.1073/pnas.0406472102

DO - 10.1073/pnas.0406472102

M3 - Article

C2 - 15821030

AN - SCOPUS:17644377914

VL - 102

SP - 5685

EP - 5690

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 16

ER -