The EH (for Eps15 Homology) domain is a protein-protein interaction module of approximately 95 residues which was originally identified as a repeated sequence present in three copies at the N terminus of the tyrosine kinase substrates Eps15 and Eps15R [ PUBMED:7568168 PUBMED:11911876 … expand

The EH (for Eps15 Homology) domain is a protein-protein interaction module of approximately 95 residues which was originally identified as a repeated sequence present in three copies at the N terminus of the tyrosine kinase substrates Eps15 and Eps15R [ PUBMED:7568168 PUBMED:11911876 ]. The EH domain was subsequently found in several proteins implicated in endocytosis, vesicle transport and signal transduction in organisms ranging from yeast to mammals. EH domains are present in one to three copies and they may include calcium-binding domains of the EF-hand type [ PUBMED:9397678 PUBMED:10021353 ]. Eps15 is divided into three domains: domain I contains signatures of a regulatory domain, including a candidate tyrosine phosphorylation site and EF-hand-type calcium-binding domains, domain II presents the characteristic heptad repeats of coiled-coil rod-like proteins, and domain III displays a repeated aspartic acid-proline-phenylalanine motif similar to a consensus sequence of several methylases [ PUBMED:7689153 ].

EH domains have been shown to bind specifically but with moderate affinity to peptides containing short, unmodified motifs through predominantly hydrophobic interactions. The target motifs are divided into three classes: class I consists of the concensus Asn-Pro-Phe (NPF) sequence; class II consists of aromatic and hydrophobic di- and tripeptide motifs, including the Phe-Trp (FW), Trp-Trp (WW), and Ser-Trp-Gly (SWG) motifs; and class III contains the His-(Thr/Ser)-Phe motif (HTF/HSF) [ PUBMED:9303539 PUBMED:9822599 ]. The structure of several EH domains has been solved by NMR spectroscopy. The fold consists of two helix-loop-helix characteristic of EF-hand domains, connected by a short antiparallel β-sheet. The target peptide is bound in a hydrophobic pocket between two α helices. Sequence analysis and structural data indicate that not all the EF-hands are capable of binding calcium because of substitutions of the calcium-liganding residues in the loop [ PUBMED:9721102 PUBMED:10757979 PUBMED:11389591 ].