The disabled 1 phosphotyrosine-binding domain binds to the internalizationsignals of transmembrane glycoproteins and to phospholipids

Disabled gene products are important for nervous system development in dros ophila and mammals. In mice, the Dab1 protein is thought to function downst ream of the extracellular protein Reln during neuronal positioning. The str uctures of Dab proteins suggest that they mediate protein-protein or protei n-membrane docking functions. Here we show that the amino-terminal phosphot yrosine-binding (PTB) domain of Dab1 binds to the transmembrane glycoprotei ns of the amyloid precursor protein (APP) and low-density lipoprotein recep tor families and the cytoplasmic signaling protein Ship. Dab1 associates wi th the APP cytoplasmic domain in transfected cells and is coexpressed with APP in hippocampal neurons. Screening of a set of altered peptide sequences showed that the sequence GYXNPXY present in APP family members is an optim al binding sequence, with approximately 0.5 mu M affinity. Unlike other PTB domains, the Dab1 PTB does not bind to tyrosine-phosphorylated peptide lig ands. The PTB domain also binds specifically to phospholipid bilayers conta ining phosphatidylinositol 4P (PtdIns4P) or PtdIns4,5P(2) in a manner that does not interfere with protein binding. We propose that the PTB domain per mits Dab1 to bind specifically to transmembrane proteins containing an NPXY internalization signal.