Origins of peptide selectivity and phosphoinositide binding revealed by structures of Disabled-1 PTB domain complexes

Peggy C. Stolt, Hyesung Jeon, Hyun Kyu Song, Joachim Herz, Michael J. Eck, Stephen C. Blacklow

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

Formation of the mammalian six-layered neocortex depends on a signaling pathway that involves Reelin, the very low-density lipoprotein receptor, the apolipoprotein E receptor-2 (ApoER2), and the adaptor protein Disabled-1 (Dab1). The 1.5 Å crystal structure of a complex between the Dab1 phosphotyrosine binding (PTB) domain and a 14-residue peptide from the ApoER2 tail explains the unusual preference of Dab1 for unphosphorylated tyrosine within the NPxY motif of the peptide. Crystals of the complex soaked with the phosphoinositide PI-4,5P2 (PI) show that PI binds to conserved basic residues on the PTB domain opposite the peptide binding groove. This finding explains how the Dab1 PTB domain can simultaneously bind PI and the ApoER2 tail. Recruitment of the Dab1 PTB domain to PI-rich regions of the plasma membrane may facilitate association with the Reelin receptor cytoplasmic tails to transduce a critical positional cue to migrating neurons.

Original languageEnglish (US)
Pages (from-to)569-579
Number of pages11
JournalStructure
Volume11
Issue number5
DOIs
StatePublished - May 1 2003

Fingerprint

Phosphotyrosine
Phosphatidylinositols
Peptides
Neocortex
Cues
Tyrosine
Cell Membrane
Neurons
low density lipoprotein receptor-related protein 8
Proteins

Keywords

  • ApoER2
  • Disabled
  • Lipoprotein receptor
  • Phosphoinositide
  • Reelin signaling
  • X-ray crystallography

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Origins of peptide selectivity and phosphoinositide binding revealed by structures of Disabled-1 PTB domain complexes. / Stolt, Peggy C.; Jeon, Hyesung; Song, Hyun Kyu; Herz, Joachim; Eck, Michael J.; Blacklow, Stephen C.

In: Structure, Vol. 11, No. 5, 01.05.2003, p. 569-579.

Research output: Contribution to journalArticle

Stolt, Peggy C. ; Jeon, Hyesung ; Song, Hyun Kyu ; Herz, Joachim ; Eck, Michael J. ; Blacklow, Stephen C. / Origins of peptide selectivity and phosphoinositide binding revealed by structures of Disabled-1 PTB domain complexes. In: Structure. 2003 ; Vol. 11, No. 5. pp. 569-579.
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