The VHS domain of human Tom1.
The approximately 150 amino acid VHS (Vps27p, Hrs and STAM) domain has been identified from over 40 different eukaryotic proteins. VHS domains can be found in the context of other modular domains such as the SH3 domain and the FYVE domain in EAST and Hrs proteins, respectively. This domain is also found at the amino-terminus of several proteins implicated in receptor tyrosine kinases (RTK) signaling. VHS domains are found in proteins linked to RTK-mediated endocytosis, such as STAM, EAST and Hrs. The VHS domain of GGA proteins binds to an acidic di-leucine motif in the cytoplasmic domain of sorting receptors, including the mannose 6-phosphate receptor. GGA proteins are required for the targeting of mannose 6-phosphate receptor to the lysosome, where the receptor functions to mediate lysosomal enzyme sorting.
The three dimensional structure of the VHS domains from Drosophila Hrs and the human Target of Myb1, Tom1, have been solved. The VHS domain is comprised of eight α helices that fold into a right-handed, superhelical structure. The core VHS domain consists almost exclusively of hydrophobic residues, with polar, acidic, and basic residues restricted to the domain surface. The Hrs1 protein forms a pyramid-like structure, with the VHS superhelical structure forming the base while the FYVE domain sits on top. The VHS domain shares structural similarity with HEAT and ARM repeats, two additional protein-protein interaction motifs, and also resembles the ENTH domain, which is found in proteins involved in vesicle trafficking (ie. Epsins, CALM, and AP-180).
| VHS Domain Proteins | Binding Partners |
| Hrs | Hrs FYVE domain |
