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ENTH Domain

Class: Phospholipid binding 


No ImageDespite low primary sequence similarity, the solved structures of various ENTH domains are very similar and are composed of eight alpha helices connected by loops of varying lengths. Three helical hairpins (a1-2, a3-4, and a6-7) are stacked consecutively with a right-handed twist, conferring a rectangular topology to the ENTH domain. A cleft of positively charged residues contributes to phoshoinositide binding. Clusters of basic amino acids present in some but not all ENTH family members (AP180/CALM) have been shown to enrich the affinity for phosphoinositides.

Structure Reference:
Hyman, J. (2000) J. Cell Biol. 149(3), 537-46. PDB: 1EDU.

Domain binding and function:
First identified in the endocytotic protein epsin 1, the epsin NH2-terminal homology (ENTH) domain is a membrane binding motif of approximately 150 amino acids. Proteins containing this domain have been shown to bind to phospholipids including PtdIns(4,5)P2 and PtdIns(1,4,5)P3. Consistent with these findings, the primary function suggested for ENTH domain containing proteins is to act as clathrin adaptors in endocytosis, with binding of the ENTH domain to the phospholipid bilayer allowing recruitment of clathrin components and clathrin accessory factors to the cell membrane. In addition, two ENTH containing proteins (HIP1, HIP1R), shown to localize to clathrin coated pits, also contain a putative actin binding motif (ILWEQ) providing evidence for the elusive link between the actin cytoskeleton and endocytosis.
Examples of Proteins: 
ENTH Domain Proteins
Binding partner
Epsin1          PtdIns(4,5)P2 / PtdIns(1,4,5)P3
AP180          PtdIns(4,5)P2 / PtdIns(1,4,5)P3

         PI(3,4)P2; PI(3,5)P2

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