Multiple modes of peptide recognition by the PTB domain of the cell fate determinant Numb

The phosphotyrosine-binding (PTB) domain of the cell fate determinant Numb is involved in the formation of multiple protein complexes in vivo and can bind a diverse array of peptide sequences in vitro. To investigate the stru ctural basis for the promiscuous nature of this protein module, we have det ermined its solution structure by NMR in a complex with a peptide containin g an NMSF sequence derived from the Numb-associated kinase (Nak). The Nak p eptide was found to adopt a significantly different structure from that of a GPpY sequence-containing peptide previously determined. In contrast to th e helical turn adopted by the GPpY peptide, the Nak peptide forms a beta-tu rn at the NMSF site followed by another turn near the C-terminus. The Numb PTB domain appears to recognize peptides that differ in both primary and se condary structures by engaging various amounts of the binding surface of th e protein. Our results suggest a mechanism through which a single PTB domai n might interact with multiple distinct target proteins to control a comple x biological process such as asymmetric cell division.