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 [1]. 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 (see <PDOC00018>) [2,3,4].

EH domains have been shown to bind specifically but with moderate affinity to peptide 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) [5,6].

The structure of several EH domains has been solved by NMR (see <PDB:1EH2>. The fold consists of two helix-loop-helix characteristic of EF-hand domains and 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 mutations of the calcium-liganding residues in the loop [7,8,9,10].

Some proteins known to contain an EH domain are listed below:

• Mammalian epidermal growth factor receptor substrate 15 (Eps15) and the Eps15 related (Eps15R) protein. They bind to the α-adaptin subunit of AP-1 which plays a major role in clathrin-mediated endocytosis.
• Vertebrate intersectins. They colocalize with clathrin and interact with a variety of endocytic proteins.
• Mammalian γ-synergin.
• Human Partner of RalBP1 protein (POB1).
• Mouse RalBP1-associated Eps-homology protein (Reps1).
• Mammalian EH-domain containing protein 1. EHD1 could play a role in receptor-mediated endocytosis.
• Mammalian EH-domain containing proteins 2 (EHD2), 3 (EHD3) and 4 (EHD4).
• Drosophila dynamin associated proteins DAP160-1 and DAP160-2, the homologues of intersectins.
• Caenorhabditis elegans ehs-1.
• Yeast PAN1, a protein required for both the endocytic process and normal organization of the cortical actin cytoskeleton.
• Yeast END3, a protein required for the internalization step of endocytosis and for actin cytoskeleton organization.

The profile we developed covers the entire EH domain.