LAUSR

Significance Src homology 2 (SH2) domains are phosphotyrosine binding motifs that play key roles in cellular signaling. There are 110 proteins in the human genome containing SH2 binding domains, of which 10 contain tandem SH2 domains. Tandem domains have been shown to improve avidity and specificity and contribute to allostery. Here, we show that tandem SH2 domains can also exhibit binding lifetimes that are accelerated by the activity of phosphatases. This accelerated unbinding requires tandem SH2 domains to engage their substrates in dynamic binding modes that cycle between single SH2-bound states. We experimentally confirm that this is the case for the well-studied kinase ZAP70 binding the T cell receptor. We suggest that accelerated unbinding is a general feature of signaling networks.