Structure of the Homer EVH1 domain-peptide complex reveals a new twist in polyproline recognition

Neuron. 2000 Apr;26(1):143-54. doi: 10.1016/s0896-6273(00)81145-9.

Abstract

Homer EVH1 (Ena/VASP Homology 1) domains interact with proline-rich motifs in the cytoplasmic regions of group 1 metabotropic glutamate receptors (mGluRs), inositol-1,4,5-trisphosphate receptors (IP3Rs), and Shank proteins. We have determined the crystal structure of the Homer EVH1 domain complexed with a peptide from mGluR (TPPSPF). In contrast to other EVH1 domains, the bound mGluR ligand assumes an unusual conformation in which the side chains of the Ser-Pro tandem are oriented away from the Homer surface, and the Phe forms a unique contact. This unusual binding mode rationalizes conserved features of both Homer and Homer ligands that are not shared by other EVH1 domains. Site-directed mutagenesis confirms the importance of specific Homer residues for ligand binding. These results establish a molecular basis for understanding the biological properties of Homer-ligand complexes.

Publication types

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

MeSH terms

  • Animals
  • Carrier Proteins / chemistry*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cytoskeletal Proteins*
  • Escherichia coli
  • Homer Scaffolding Proteins
  • Ligands
  • Microfilament Proteins
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed / genetics*
  • Neuropeptides / chemistry*
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Peptides / chemistry*
  • Peptides / genetics
  • Rats
  • Receptors, Metabotropic Glutamate / metabolism

Substances

  • Carrier Proteins
  • Cytoskeletal Proteins
  • Enah protein, mouse
  • Homer Scaffolding Proteins
  • Ligands
  • Microfilament Proteins
  • Neuropeptides
  • Peptides
  • Receptors, Metabotropic Glutamate

Associated data

  • PDB/1DDV
  • PDB/1DDW