STRUCTURE AND ASN-PRO-PHE BINDING POCKET OF THE EPS15 HOMOLOGY DOMAIN

Eps15 homology (EH) domains are eukaryotic signaling modules that reco gnize proteins containing Asn-Pro-Phe (NPF) sequences. The structure o f the central EH domain of Eps15 has been solved by heteronuclear magn etic resonance spectroscopy. The fold consists of a pair of EF hand mo tifs, the second of Which binds tightly to calcium. The NPF peptide is bound in a hydrophobic pocket between two a helices, and binding is m ediated by a critical aromatic interaction as revealed by structure-ba sed mutagenesis. The fold is predicted to be highly conserved among 30 identified EH domains and provides a structural basis for defining EH -mediated events in protein trafficking and growth factor signaling.