Linked Life Data

15066431

Source:http://linkedlifedata.com/resource/pubmed/id/15066431

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2004-4-6
pubmed:abstractText
Remodeling of the actin cytoskeleton is controlled by signaling pathways that include the Wiskott-Aldrich syndrome protein (WASP). WASP is regulated by autoinhibition, and the intramolecular contacts that inactivate the protein can be relieved through binding to the Rho-family GTPase Cdc42. Here, we show that the allosteric regulation of WASP can be quantitatively described by a two-state equilibrium between an active, largely unfolded conformation that is able to stimulate the Arp2/3 complex, and an inactive, folded conformation. The model is parameterized by the stability of WASP against unfolding and by the Cdc42 affinities of WASP constructs that mimic the unfolded and folded conformations. The model is consistent with NMR spectra of GTPase-bound WASP, and accurately predicts changes of amide hydrogen exchange behavior and Cdc42 affinity as a function of WASP stability. The results provide a thermodynamic rationale for the GTPase-independent recruitment of WASP and other autoinhibited effectors to their sites of activity. They also explain how basal activity is suppressed and confirm that WASP needs to integrate multiple cooperative inputs for maximal activation. Our analysis suggests that, in general, simple modulation of a two-state equilibrium may determine several regulatory functions, allowing the generation of complex signaling behavior in vivo.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-2836
pubmed:author
pubmed:issnType
Print
pubmed:day
23
pubmed:volume
338
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
271-85
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
A two-state allosteric model for autoinhibition rationalizes WASP signal integration and targeting.
pubmed:affiliation
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA. Matthias.Buck@case.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't