Structure of a Numb PTB domain–peptide complex suggests a basis for diverse binding specificity

SC Li, C Zwahlen, SJF Vincent, CJ McGlade… - Nature structural …, 1998 - nature.com
SC Li, C Zwahlen, SJF Vincent, CJ McGlade, LE Kay, T Pawson, JD Forman-Kay
Nature structural biology, 1998nature.com
The phosphotyrosine-binding (PTB) domain of Numb, a protein involved in asymmetric cell
division, has recently been shown to bind to the adapter protein Lnx through an LDNPAY
sequence, to the Numb-associated kinase (Nak) through a sequence that does not contain
an NPXY motif and to GP (p) Y-containing peptides obtained from library screening. We
show here that these diverse peptide sequences bind with comparable affinities to the Numb
PTB domain at a common binding site on the surface of the protein. The NMR structure of …
Abstract
The phosphotyrosine-binding (PTB) domain of Numb, a protein involved in asymmetric cell division, has recently been shown to bind to the adapter protein Lnx through an LDNPAY sequence, to the Numb-associated kinase (Nak) through a sequence that does not contain an NPXY motif and to GP (p) Y-containing peptides obtained from library screening. We show here that these diverse peptide sequences bind with comparable affinities to the Numb PTB domain at a common binding site on the surface of the protein. The NMR structure of the Numb PTB domain in complex with a GPpY-containing peptide reveals a novel mechanism of binding with the peptide in a helical turn that does not hydrogen bond to the PTB domain β-sheet. These results suggest that PTB domains can potentially have multiple modes of peptide recognition and provide a structural basis from which the multiple functions of the Numb PTB domain during asymmetric cell division could arise.
nature.com