Research ArticleBiochemistry

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

See allHide authors and affiliations

Science Signaling  15 Apr 2014:
Vol. 7, Issue 321, pp. ra35
DOI: 10.1126/scisignal.2004993

You are currently viewing the editor's summary.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Double Lock for Safety

Members of the Vav family of guanine nucleotide exchange factors activate Rho family guanosine triphosphatases to mediate processes such as lymphocyte development; however, they are also implicated in pathologies such as cancer. Interactions between N-terminal regions of Vav with its central catalytic core contribute to the formation of an autoinhibited conformation. Phosphorylation of specific N-terminal tyrosines disrupts this interaction and leads to Vav activation. Through mutational analysis and nucleotide exchange assays, Barreira et al. showed that there is a second inhibitory interaction with the catalytic core that is mediated by a C-terminal Src homology 3 (CSH3) domain of Vav1. Furthermore, phosphorylation of distinct tyrosines disrupted this interaction. Thus, both sets of inhibitory interactions constitute a double-lock system that prevents spurious activation of Vav1 by requiring multiple phosphorylation events to relieve autoinhibition.

View Full Text