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

Jutta Beneken, Jian Cheng Tu, Bo Xiao, Mutsuo Nuriya, Joseph P. Yuan, Paul F. Worley, Daniel J. Leahy

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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.

Original languageEnglish
Pages (from-to)143-154
Number of pages12
JournalNeuron
Volume26
Issue number1
DOIs
Publication statusPublished - 1 Jan 2000

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Beneken, J., Tu, J. C., Xiao, B., Nuriya, M., Yuan, J. P., Worley, P. F., & Leahy, D. J. (2000). Structure of the Homer EVH1 domain-peptide complex reveals a new twist in polyproline recognition. Neuron, 26(1), 143-154. https://doi.org/10.1016/S0896-6273(00)81145-9