Crystal structures of the Dab homology domains of mouse disabled 1 and 2

J Biol Chem. 2003 Sep 19;278(38):36572-81. doi: 10.1074/jbc.M304384200. Epub 2003 Jun 24.

Abstract

Disabled (Dab) 1 and 2 are mammalian homologues of Drosophila DAB. Dab1 is a key cytoplasmic mediator in Reelin signaling that controls cell positioning in the developing central nervous system, whereas Dab2 is an adapter protein that plays a role in endocytosis. DAB family proteins possess an amino-terminal DAB homology (DH) domain that is similar to the phosphotyrosine binding/phosphotyrosine interaction (PTB/PI) domain. We have solved the structures of the DH domains of Dab2 (Dab2-DH) and Dab1 (Dab1-DH) in three different ligand forms, ligand-free Dab2-DH, the binary complex of Dab2-DH with the Asn-Pro-X-Tyr (NPXY) peptide of amyloid precursor protein (APP), and the ternary complex of Dab1-DH with the APP peptide and inositol 1,4,5-trisphosphate (Ins-1,4,5-P3, the head group of phosphatidylinositol-4,5-diphosphate (PtdIns-4,5-P2)). The similarity of these structures suggests that the rigid Dab DH domain maintains two independent pockets for binding of the APP/lipoprotein receptors and phosphoinositides. Mutagenesis confirmed the structural determinants specific for the NPXY sequence and PtdIns-4,5-P2 binding. NMR spectroscopy confirmed that the DH domain binds to Ins-1,4,5-P3 independent of the NPXY peptides. These findings suggest that simultaneous interaction of the rigid DH domain with the NPXY sequence and PtdIns-4,5-P2 plays a role in the attachment of Dab proteins to the APP/lipoprotein receptors and phosphoinositide-rich membranes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport / chemistry*
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Amyloid beta-Protein Precursor / chemistry
  • Animals
  • Apoptosis Regulatory Proteins
  • Binding Sites
  • Cell Membrane / metabolism
  • Crystallography, X-Ray
  • DNA, Complementary / metabolism
  • Genes, Tumor Suppressor
  • Inositol 1,4,5-Trisphosphate / chemistry
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Mice
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Mutation
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / metabolism
  • Peptides / chemistry
  • Phosphatidylinositol 4,5-Diphosphate / chemistry
  • Phospholipids / chemistry
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins / chemistry*
  • Proteins / metabolism
  • Signal Transduction
  • Tumor Suppressor Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Amyloid beta-Protein Precursor
  • Apoptosis Regulatory Proteins
  • DAB2 protein, human
  • DNA, Complementary
  • Dab1 protein, mouse
  • Dab2 protein, mouse
  • Ligands
  • Nerve Tissue Proteins
  • Peptides
  • Phosphatidylinositol 4,5-Diphosphate
  • Phospholipids
  • Proteins
  • Tumor Suppressor Proteins
  • Inositol 1,4,5-Trisphosphate

Associated data

  • PDB/1M7E
  • PDB/1OQN
  • PDB/1P3R