Family

Ubiquitin binding protein, Hrs/VPS27 (IPR017073)

Short name: Ubi-bd_Hrs_VPS27

Overlapping homologous superfamilies

None.

Family relationships

None.

Description

Members of this group are characterised by the presence of a VHS (Vps27p/Hrs/Stam) domain in the N-terminal portion followed by a FYVE domain and one or two ubiquitin-interacting motifs.

VHS domains are found at the N termini of select proteins involved in intracellular membrane trafficking and are often localised to membranes. FYVE domains are membrane localisation domains that specifically bind phosphatidylinositol 3-phosphate, regulating membrane trafficking and signalling pathways [PMID: 9697764]. The ubiquitin-interacting motif is found in many proteins involved in the endocytic pathway and is capable of binding ubiquitin.

The three dimensional structure of the VHS and FYVE tandem domain unit of Drosophila melanogaster (Fruit fly) Hrs reveals a pyramidal structure in which the much larger VHS domain forms a rectangular base and the FYVE domain occupies the apical end. The VHS domain is composed of an unusual superhelix of eight alpha helices, and the FYVE domain is mainly built of loops, two double-stranded antiparallel sheets, and a helix stabilised by two tetrahedrally coordinated zinc atoms. Dimerisation creates two identical pockets designed for binding ligands with multiple negative charges such as citrate or phosphatidylinositol 3-phosphate [PMID: 10693761]. The FYVE domain of the Hrs orthologue in yeast is consistent with this structure [PMID: 10367894].

Members of this group regulate endosome maturation and trafficking between endosomes and the degradative organelles (lysosome/vacuole) [PMID: 10092582]. Monoubiquitination functions as a signal for sorting transmembrane proteins into intraluminal vesicles of multivesicular bodies (MVB) and subsequent delivery to the degradative organelles [PMID: 11555416]. The sorting of proteins into the inner vesicles of multivesicular bodies is required for many key cellular processes, ranging from the downregulation of activated signalling receptors to the proper stimulation of the immune response [PMID: 14624836, PMID: 11832215]. A molecular machine that contains the ubiquitin-binding protein Hrs as well as three multi-subunit complexes, ESCRT (endosome-associated complex required for transport) -I, -II and -III, are essential for both sorting and MVB formation [PMID: 12892785, PMID: 12461556].

A conserved sequence motif, PT/(S)AP, found in structural proteins of several RNA viruses (e.g. HIV gag), promotes release of virus from the cell by recruiting the ESCRT machinery to the viral budding sites at the plasma membrane. The same motif is also found in Hrs and recruits the ESCRT I complex to endosomes through direct interaction with one of its components, TSG101. Fusion of Hrs with the gag gene of HIV-1 lacking this motif can complement a defect in virus budding. Further challenging data indicate a wider role for Hrs in the regulation of endosome dynamics [PMID: 14624836].

Rat GalCer expression factor 1 (GEF-1), which shows high sequence similarity to Hrs, induces GalCer expression, morphological changes, and cell growth inhibition in COS-7 cells [PMID: 11555619].

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.
PIRSF