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

Nat Struct Biol. 1998 Dec;5(12):1075-83. doi: 10.1038/4185.

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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Carrier Proteins / metabolism
  • Cell Division
  • Drosophila
  • Drosophila Proteins
  • Hydrogen Bonding
  • Juvenile Hormones / metabolism*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / metabolism
  • Phosphotyrosine / metabolism*
  • Protein Conformation
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Secondary

Substances

  • Carrier Proteins
  • Drosophila Proteins
  • Juvenile Hormones
  • Peptide Fragments
  • numb protein, Drosophila
  • Phosphotyrosine
  • Nak protein, Drosophila
  • Protein Serine-Threonine Kinases

Associated data

  • PDB/2NMB