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The C-Terminal SH3 Domain Contributes to the Intramolecular Inhibition of Vav Family Proteins -- Barreira et al. 7 (321): ra35 -- Science Signaling

The C-Terminal SH3 Domain Contributes to the Intramolecular Inhibition of Vav Family Proteins -- Barreira et al. 7 (321): ra35 -- Science Signaling



Sci. Signal., 15 April 2014

Vol. 7, Issue 321, p. ra35

[DOI: 10.1126/scisignal.2004993]
RESEARCH ARTICLES

The C-Terminal SH3 Domain Contributes to the Intramolecular Inhibition of Vav Family Proteins

María Barreira1,2, Salvatore Fabbiano1,2*, José R. Couceiro1,2*, Eva Torreira3, Jorge L. Martínez-Torrecuadrada4, Guillermo Montoya5, Oscar Llorca3, and Xosé R. Bustelo1,2{dagger}
1 Centro de Investigación del Cáncer, Campus Unamuno, E37007 Salamanca, Spain.

2 Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)–University of Salamanca, Campus Unamuno, E37007 Salamanca, Spain.

3 Centro de Investigaciones Biológicas, CSIC, 9 Ramiro de Maeztu Street, E28040 Madrid, Spain.

4 Biotechnology Programme, Centro Nacional de Investigaciones Oncológicas, 3 Melchor Fernández Almagro Street, E28029 Madrid, Spain.

5 Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, E28029 Madrid, Spain.
* These authors contributed equally to this work.

Abstract: Vav proteins are phosphorylation-dependent guanine nucleotide exchange factors (GEFs) that catalyze the activation of members of the Rho family of guanosine triphosphatases (GTPases). The current regulatory model holds that the nonphosphorylated, catalytically inactive state of these GEFs is maintained by intramolecular interactions among the amino-terminal domains and the central catalytic core, which block the binding of Vav proteins to GTPases. We showed that this autoinhibition is mechanistically more complex, also involving the bivalent association of the carboxyl-terminal Src homology 3 (SH3) region of Vav with its catalytic and pleckstrin homology (PH) domains. Such interactions occurred through proline-rich region–independent mechanisms. Full release from this double-locked state required synergistic weakening effects from multiple phosphorylated tyrosine residues, thus providing an optimized system to generate gradients of Vav GEF activity depending on upstream signaling inputs. This mechanism is shared by mammalian and Drosophila melanogaster Vav proteins, suggesting that it may be a common regulatory feature for this protein family.


{dagger} Corresponding author. E-mail: xbustelo@usal.es
Citation: M. Barreira, S. Fabbiano, J. R. Couceiro, E. Torreira, J. L. Martínez-Torrecuadrada, G. Montoya, O. Llorca, X. R. Bustelo, The C-Terminal SH3 Domain Contributes to the Intramolecular Inhibition of Vav Family Proteins. Sci. Signal. 7, ra35 (2014).
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