Article
- The EMBO Journal (2005) 24, 1330 - 1340
- doi:10.1038/sj.emboj.7600617
Published online: 10 March 2005
Subject Categories:
Global conformational rearrangements during the activation of the GDP/GTP exchange factor Vav3
Óscar Llorca1,a, Ernesto Arias-Palomo1,a, José L Zugaza2,a and Xosé R Bustelo2
- Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
- Centro de Investigación del Cáncer, University of Salamanca-CSIC, Campus Unamuno, Salamanca, Spain
Correspondence to:
Xosé R Bustelo, Centro de Investigación del Cáncer, University of Salamanca-CSIC, Campus Unamuno, 37007 Salamanca, Spain. Tel.: +34 923 29 4802; Fax: +34 923 29 4743; E-mail: xbustelo@usal.es
aThese authors contributed equally to this work
Received 17 December 2004; Accepted 7 February 2005
Abstract
Activation of Rho/Rac GTPases during cell signaling requires the participation of GDP/GTP exchange factors of the Dbl family. Although the structure of the catalytic core of Dbl proteins has been established recently, the molecular changes that the full-length proteins experience during normal or oncogenic conditions of stimulation are still unknown. Here, we have used single-particle electron microscopy to solve the structures of the inactive (unphosphorylated), active (phosphorylated), and constitutively active (N-terminally deleted) versions of the exchange factor Vav3. Comparison of these forms has revealed the interdomain interactions maintaining the inactive Vav3 state and the dynamic changes that the overall Vav3 structure undergoes upon tyrosine phosphorylation. We have also found that the conformations of phosphorylated Vav3 and N-terminally deleted Vav3 are distinct, indicating that the acquisition of constitutive activity by exchange factors is structurally more complex than the mere elimination of inhibitory interactions between structural domains.
Keywords:
- electron microscopy,
- GDP–GTP exchange factors,
- Rac,
- Vav
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