Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation Journal Article

  

Authors:	Aghazadeh, B.; Lowry, W. E.; Huang, X. Y.; Rosen, M. K.
Article Title:	Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation
Abstract:	Rho-family GTPases transduce signals from receptors leading to changes in cell shape and motility, mitogenesis, and development. Proteins containing the Dbl homology (DH) domain are responsible for activating Rho GTPases by catalyzing the exchange of GDP for GTP. Receptor-initiated stimulation of Dbl protein Vav exchange activity involves tyrosine phosphorylation. We show through structure determination that the mVav1 DH domain is autoinhibited by an N-terminal extension, which lies in the GTPase interaction site. This extension contains the Tyr174 Src-family kinase recognition site, and phosphorylation or truncation of this peptide results in stimulation of GEF activity. NMR spectroscopy data show that the N-terminal peptide is released from the DH domain and becomes unstructured upon phosphorylation. Thus, tyrosine phosphorylation relieves autoinhibition by exposing the GTPase interaction surface of the DH domain, which is obligatory for Vav activation.
Keywords:	protein phosphorylation; proto-oncogene proteins; animals; cell cycle proteins; mice; gene targeting; proto oncogene; models, biological; enzyme activation; structure-activity relationship; phosphorylation; sequence homology, amino acid; nucleotide sequence; peptide fragments; nuclear magnetic resonance spectroscopy; models, molecular; protein structure, tertiary; binding sites; catalysis; cell shape; sequence homology; feedback; src-family kinases; guanosine triphosphate; protein structure, secondary; receptor binding; amino acid motifs; phosphotyrosine; nuclear magnetic resonance, biomolecular; cdc42 gtp-binding protein; rac1 gtp-binding protein; proto-oncogene proteins c-vav; priority journal; article; motor development
Journal Title:	Cell
Volume:	102
Issue:	5
ISSN:	0092-8674
Publisher:	Cell Press
Date Published:	2000-09-01
Start Page:	625
End Page:	633
Language:	English
PUBMED:	11007481
PROVIDER:	scopus
DOI:	10.1016/S0092-8674(00)00085-4
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-0034269240&partnerID=40&md5=1db0602e2660ca421a7449da3b2ceb3b
Notes:	Export Date: 18 November 2015 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/84190