Bond swapping from a charge cloud allows flexible coordination of upstream signals through WASP: Multiple regulatory roles for the WASP basic region.
dc.contributor.author | Tetley, George JN | |
dc.contributor.author | Szeto, Aydan | |
dc.contributor.author | Fountain, Adam J | |
dc.contributor.author | Mott, Helen R | |
dc.contributor.author | Owen, Darerca | |
dc.date.accessioned | 2018-11-10T00:30:15Z | |
dc.date.available | 2018-11-10T00:30:15Z | |
dc.date.issued | 2018-09-28 | |
dc.identifier.issn | 0021-9258 | |
dc.identifier.uri | https://www.repository.cam.ac.uk/handle/1810/284894 | |
dc.description.abstract | Wiskott-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.medium | Print-Electronic | |
dc.language | eng | |
dc.publisher | Elsevier BV | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Neoplasms | |
dc.subject | Wiskott-Aldrich Syndrome | |
dc.subject | Actins | |
dc.subject | ras Proteins | |
dc.subject | cdc42 GTP-Binding Protein | |
dc.subject | Crystallography, X-Ray | |
dc.subject | Signal Transduction | |
dc.subject | Binding Sites | |
dc.subject | Amino Acid Sequence | |
dc.subject | Regulatory Sequences, Nucleic Acid | |
dc.subject | Protein Binding | |
dc.subject | Kinetics | |
dc.subject | Wiskott-Aldrich Syndrome Protein | |
dc.title | Bond swapping from a charge cloud allows flexible coordination of upstream signals through WASP: Multiple regulatory roles for the WASP basic region. | |
dc.type | Article | |
prism.endingPage | 15151 | |
prism.issueIdentifier | 39 | |
prism.publicationDate | 2018 | |
prism.publicationName | J Biol Chem | |
prism.startingPage | 15136 | |
prism.volume | 293 | |
dc.identifier.doi | 10.17863/CAM.32264 | |
dcterms.dateAccepted | 2018-08-13 | |
rioxxterms.versionofrecord | 10.1074/jbc.RA118.003290 | |
rioxxterms.licenseref.uri | http://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2018-09 | |
dc.contributor.orcid | Owen, Darerca [0000-0003-0978-5425] | |
dc.identifier.eissn | 1083-351X | |
rioxxterms.type | Journal Article/Review | |
pubs.funder-project-id | MRC (MR/K017101/1) | |
cam.issuedOnline | 2018-08-13 |
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