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dc.contributor.authorTetley, George JN
dc.contributor.authorSzeto, Aydan
dc.contributor.authorFountain, Adam J
dc.contributor.authorMott, Helen
dc.contributor.authorOwen, Darerca
dc.date.accessioned2018-11-10T00:30:15Z
dc.date.available2018-11-10T00:30:15Z
dc.date.issued2018-09-28
dc.identifier.issn0021-9258
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284894
dc.description.abstractWiskott-Aldrich syndrome protein (WASP) activates the actin-related protein 2/3 homolog (Arp2/3) complex and regulates actin polymerization in a physiological setting. Cell division cycle 42 (Cdc42) is a key activator of WASP, which binds Cdc42 through a Cdc42/Rac-interactive binding (CRIB)-containing region that defines a subset of Cdc42 effectors. Here, using site-directed mutagenesis and binding affinity determination and kinetic assays, we report the results of an investigation into the energetic contributions of individual WASP residues to both the Cdc42-WASP binding interface and the kinetics of complex formation. Our results support the previously proposed dock-and-coalesce binding mechanism, initiated by electrostatic steering driven by WASP's basic region and followed by a coalescence phase likely driven by the conserved CRIB motif. The WASP basic region, however, appears also to play a role in the final complex, as its mutation affected both on- and off-rates, suggesting a more comprehensive physiological role for this region centered on the C-terminal triad of positive residues. These results highlight the expanding roles of the basic region in WASP and other CRIB-containing effector proteins in regulating complex cellular processes and coordinating multiple input signals. The data presented improve our understanding of the Cdc42-WASP interface and also add to the body of information available for Cdc42-effector complex formation, therapeutic targeting of which has promise for Ras-driven cancers. Our findings suggest that combining high-affinity peptide-binding sequences with short electrostatic steering sequences could increase the efficacy of peptidomimetic candidates designed to interfere with Cdc42 signaling in cancer.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectWiskott-Aldrich Syndrome
dc.subjectActins
dc.subjectras Proteins
dc.subjectcdc42 GTP-Binding Protein
dc.subjectCrystallography, X-Ray
dc.subjectSignal Transduction
dc.subjectBinding Sites
dc.subjectAmino Acid Sequence
dc.subjectRegulatory Sequences, Nucleic Acid
dc.subjectProtein Binding
dc.subjectKinetics
dc.subjectWiskott-Aldrich Syndrome Protein
dc.titleBond swapping from a charge cloud allows flexible coordination of upstream signals through WASP: Multiple regulatory roles for the WASP basic region.
dc.typeArticle
prism.endingPage15151
prism.issueIdentifier39
prism.publicationDate2018
prism.publicationNameJ Biol Chem
prism.startingPage15136
prism.volume293
dc.identifier.doi10.17863/CAM.32264
dcterms.dateAccepted2018-08-13
rioxxterms.versionofrecord10.1074/jbc.RA118.003290
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09
dc.contributor.orcidMott, Helen [0000-0002-7890-7097]
dc.contributor.orcidOwen, Darerca [0000-0003-0978-5425]
dc.identifier.eissn1083-351X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMRC (MR/K017101/1)
cam.issuedOnline2018-08-13


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International