EVH1 Domain Structure and Function

The EVH1 domain adopts a structure similar to pleckstrin homology (PH) domains. However, EVH1 domains do not bind to phospholipids. Instead, they mediate specific protein-protein interactions with proline-rich short peptide motifs. This interaction is important for the recruitment of EVH1 domain-harbouring proteins to specific subcellular locations and to membrane receptor complexes. According to their ligand specificity, they can be divided into four classes. Class-I EVH1 domains bind to a peptide with the consensus sequence (D/E)-(F/W/Y/L)-P-P-P-P-X-(D/E)-(D/E)-(D/E)-L. Class-II EVH1 domains found in Homer/Vesl proteins bind to the consensus sequence PPXX(F/W/Y)XD. Class-III EVH1 domains are found in N-WASP and WASP, and are also called WH1 domains. They mediate specific binding to a considerably longer EVH1-ligand found in WIP and WIP-related proteins (Volkman et al. 2002; Zettl and Way 2002; Peterson et al. 2007). The last class consists of the EVH1 domains found in Spred proteins, for which there are no known ligands. However, the crystal structure of the Spred EVH1 domain indicates that it represents a fourth distinct EVH1 class (Bundschu et al. 2006; Harmer et al. 2005; Wakioka et al. 2001). In this review, we will concentrate on the class-I EVH1 domain that is found exclusively in Ena/VASP proteins.

The EVH1 domain is composed of two anti-parallel beta sheets followed by a C-terminal alpha helix. The proline-rich peptide adopts a left-handed poly-L-proline II helix that binds primarily to aromatic amino acids within a deep grove formed by beta-strands within the EVH1 domain (Fedorov et al. 1999; Prehoda et al. 1999). This binding modus is similar to the interaction of SH3 and WW domains and Profilin with their proline-rich ligands. However, the binding surfaces in these domains are flat compared to the deep grove found in the EVH1 domain. Furthermore, specificity in the binding of the class-I EVH1 domain to its ligands is ensured by the aromatic residue N-terminal of the poly-L-proline helix and the acidic residues flanking both sides of it (Niebuhr et al. 1997; Carl et al. 1999; Fedorov et al. 1999; Prehoda et al. 1999; Ball et al. 2000). EVH1 class-I domain binding sites are found in several proteins (see Table 1) and mediate recruitment of Ena/VASP proteins to specific subcellular sites and receptor complexes.

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