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

Aghazadeh, B ; Lowry, WE ; et al.

In: Cell, Jg. 102 (2000-09-01), Heft 5, S. 625-33

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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.

Titel:	Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation.
Autor/in / Beteiligte Person:	Aghazadeh, B ; Lowry, WE ; Huang, XY ; Rosen, MK
Link:	Full Text Finder (Volltext)
Zeitschrift:	Cell, Jg. 102 (2000-09-01), Heft 5, S. 625-33
Veröffentlichung:	Cambridge, Ma : Cell Press ; <i>Original Publication</i>: Cambridge, MIT Press., 2000
Medientyp:	academicJournal
ISSN:	0092-8674 (print)
DOI:	10.1016/s0092-8674(00)00085-4
Schlagwort:	Amino Acid Motifs Animals Binding Sites Enzyme Activation Feedback Guanosine Triphosphate metabolism Mice Models, Biological Models, Molecular Nuclear Magnetic Resonance, Biomolecular Phosphorylation Protein Structure, Secondary Protein Structure, Tertiary Proto-Oncogene Proteins c-vav Structure-Activity Relationship cdc42 GTP-Binding Protein metabolism rac1 GTP-Binding Protein metabolism src-Family Kinases metabolism Cell Cycle Proteins Peptide Fragments chemistry Peptide Fragments metabolism Phosphotyrosine metabolism Proto-Oncogene Proteins chemistry Proto-Oncogene Proteins metabolism Sequence Homology, Amino Acid
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S. Language: English [Cell] 2000 Sep 01; Vol. 102 (5), pp. 625-33. MeSH Terms: Cell Cycle Proteins* ; Sequence Homology, Amino Acid* ; Peptide Fragments / chemistry ; Peptide Fragments / metabolism ; Phosphotyrosine / metabolism ; Proto-Oncogene Proteins / chemistry ; Proto-Oncogene Proteins / *metabolism ; Amino Acid Motifs ; Animals ; Binding Sites ; Enzyme Activation ; Feedback ; Guanosine Triphosphate / metabolism ; Mice ; Models, Biological ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Phosphorylation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-vav ; Structure-Activity Relationship ; cdc42 GTP-Binding Protein / metabolism ; rac1 GTP-Binding Protein / metabolism ; src-Family Kinases / metabolism Molecular Sequence: PDB 1F5X Substance Nomenclature: 0 (Cell Cycle Proteins) ; 0 (Peptide Fragments) ; 0 (Proto-Oncogene Proteins) ; 0 (Proto-Oncogene Proteins c-vav) ; 0 (Vav1 protein, mouse) ; 21820-51-9 (Phosphotyrosine) ; 86-01-1 (Guanosine Triphosphate) ; EC 2.7.10.2 (src-Family Kinases) ; EC 3.6.5.2 (cdc42 GTP-Binding Protein) ; EC 3.6.5.2 (rac1 GTP-Binding Protein) Entry Date(s): Date Created: 20000928 Date Completed: 20001004 Latest Revision: 20190705 Update Code: 20231215

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