Structure of the Homer EVH1 domain-peptide complex reveals a new twist in polyproline recognition.
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.
Beneken
J
J
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Tu
J C
JC
Xiao
B
B
Nuriya
M
M
Yuan
J P
JP
Worley
P F
PF
Leahy
D J
DJ
D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004926:Escherichia coli; D000072233:Homer Scaffolding Proteins; D008024:Ligands; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000235:genetics*; D009479:Neuropeptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C102176:Enah protein, mouse; D000072233:Homer Scaffolding Proteins; D008024:Ligands; D008840:Microfilament Proteins; D009479:Neuropeptides; D010455:Peptides; D018094:Receptors, Metabotropic Glutamate