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EH Domain

No ImageThe structure of the EH domain consists of two associated helix-loop-helix motifs separated by a short β-sheet. The αA helix lies roughly perpendicular to the other three helices (αB-D) where the αC helix lies diagonal between helices αB and αD. The juxtaposition of the N and C-termini results in the close association of tandem EH domains, and the cooperative and multivalent binding of ligand proteins. A hydrophobic pocket is formed between helices αB and αC where target peptides are believed to interact. A calcium ion is suggested to bind near the βB strand, however, not all EH domains are capable of calcium binding due to substitutions of the calcium-binding residues.
Structure Reference:

De Beer, T. et al. (1998) Science 281(5381), 1357-1360. PDB: 1EH2.

Domain binding and function:
 structureThe EH domain is a module of ~100 amino acids originally identified in the tyrosine kinase substrate Eps15, and thus termed the Eps15-Homology (EH) domain. There is considerable evidence to suggest that EH domain proteins are primarily involved in regulating endocytosis and vesicle transport. Typically, EH domains recognize peptides with core NPF motifs. Most EH proteins have multiple copies of the EH domain, and may bind cooperatively to proteins with several NPF motifs. EH domain proteins frequently have other repeated motifs (i.e., DPF, PXXP, coiled-coil) and modules (i.e., SH3 domains), suggesting that they may serve a scaffolding function in endocytosis. Indeed, the DPF motifs of Eps15 interact with the N-terminal appendage region of the clathrin adaptor AP-2 component, alpha-Adaptin. Eps15, and other EH domain proteins such as Intersectin, can bind proteins implicated in endocytosis, such as the GTPase Dynamin and the lipid phosphatase Synaptojanin. Genetic data in yeast have directly demonstrated the importance of an EH domain protein, Pan1, in endocytosis.
Examples of Proteins: 
EH domain protein
Binding partner
Eps15 Epsin, scaffolding protein with ENTH domain
Eps15 Synaptojanin, phosphatidylinositol 5'- phosphatase

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