Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition

SAP, the product of the gene mutated in X-linked lymphoproliferative syndro me (XLP), consists of a single SH2 domain that has been shown to bind the c ytoplasmic tail of the lymphocyte coreceptor SLAM. Here we describe structu res that show that SAP binds phosphorylated and nonphosphorylated SLAM pept ides in a similar mode, with the tyrosine or phosphotyrosine residue insert ed into the phosphotyrosine-binding pocket. We find that specific interacti ons with residues N-terminal to the tyrosine, in addition to more character istic C-terminal interactions, stabilize the complexes. A phosphopeptide li brary screen and analysis of mutations identified in XLP patients confirm t hat these extended interactions are required for SAP function. Further, we show that SAP and the similar protein EAT-2 recognize the sequence motif Tl pYXX(V/I).