Structural basis for a novel interaction between TXNIP and Vav2.

Thioredoxin-interacting protein (TXNIP) is a multifunctional protein involved in diverse cellular processes such as cell proliferation and apoptosis. TXNIP stability is controlled by the ubiquitin-proteasome pathway, and the E3 ubiquitin ligase Itch directly interacts with TXNIP via PPxY motifs of TXNIP. In a previously published study, we have shown that phosphorylation of the PPxY tyrosyl residue switches TXNIP selectivity between different binding partners. Here, we describe that tyrosine-phosphorylated PPxY motifs also bind to SH2 domains of Vav2 and Src with dissociation constants around 10 μm and that phosphorylation is indispensable for these interactions as well. The crystal structure of the complex between a phosphorylated PPxY motif, and the SH2 domain of Vav2 reveals a conserved recognition mechanism.