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| Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation |
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| Author(s): Aghazadeh B, Lowry WE, Huang XY, Rosen MK |
| Source: CELL Volume: 102 Issue: 5 Pages: 625-633 Published: SEP 1 2000 |
| Times Cited: 196 References: 60 |
| 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Rosen, MK (reprint author), Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, New York, NY 10021 USA |
Addresses:
1. Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, New York, NY 10021 USA
2. Cornell Univ, Weill Grad Sch Med Sci, Grad Program Physiol & Biophys, New York, NY 10021 USA
3. Cornell Univ, Weill Grad Sch Med Sci, Grad Program Neurosci, New York, NY 10021 USA
4. Cornell Univ, Weill Grad Sch Med Sci, Grad program Biochem & Struct Biol, New York, NY 10021 USA |
| Publisher: CELL PRESS, 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA |
| Subject Category: Biochemistry & Molecular Biology; Cell Biology |
| IDS Number: 350ML |
| ISSN: 0092-8674 |
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