Domain

Vacuolar protein sorting protein 36, GLUE domain (IPR021648)

Short name: GLUE_dom

Domain relationships

None.

Description

Vps36 is a subunit of ESCRT-II, a protein involved in driving protein sorting from endosomes to lysosomes. The GLUE domain of Vps36 allows for a tight interaction to occur between the protein and Vps28, a subunit of ESCRT-I. This interaction is critical for ubiquitinated cargo progression from early to late endosomes [PMID: 16615893].

The multivesicular body (MVB) protein-sorting pathway targets transmembrane proteins either for degradation or for function in the vacuole/lysosomes. The signal for entry into this pathway is monoubiquitination of protein cargo, which results in incorporation of cargo into luminal vesicles at late endosomes. Another crucial player is phosphatidylinositol 3-phosphate (PtdINS(3)P), which is enriched on early endosomes and on the luminal vesicles of MVBs. The ESCRT complexes are critical for MVB budding and sorting of monoubiquitinated cargo into the luminal vesicles. Various Ub-binding domains (UBDs), such as UIM, UEV and NZF are found in such machineries. The Vps 36 subunit of the ESCRT-II trafficking complex binds both phosphoinositides and ubiquitin. All members of the Vps36 family contain a divergent GRAM/PH-like domain and yeast and some other fungi have one or two NZF domains inserted in the GRAM/PH-like domain.

The N-terminal region of Vps36 (EAP45) has been named the GLUE (GRAM-like ubiquitin-binding in EAP45) domain. The GLUE domain acts as a central cog driving the endosomal ESCRT machinery, through simultaneous interactions with PtdIns3P-containing membranes, ubiquitin, and ESCRT-I. Like other known ubiquitin-binding domains, the GLUE domain interacts with the hydrophobic surface patch of ubiquitin. The GLUE domain is the first ubiquitin-binding domain shown to bind phosphoinositides, and the ability of the same domain to bind both ubiquitin and a phosphoinositide opens interesting possibilities for coordination of membrane interactions and cargo recognition [PMID: 15755741, PMID: 16615893, PMID: 17057714, PMID: 16615903, PMID: 17034365].

The GLUE domain has a split PH-domain fold with two curved beta sheets and one long alpha helix. The two sheets (beta1-beta4 and beta5- beta7) form a beta barrel-like structure, the C-terminal alpha helix is wedged between the two beta sheets, covering a hydrophobic core. The Vps36 GLUE domain binds PtdIns3P via a positively charged lipid binding pocket, delineated by the variable loops beta1/beta2, beta5/beta6 and beta7/alpha1, in contrast to the vast majority of characterised PH domains, which use a different lipid binding pocket [PMID: 16615893, PMID: 17057714].

GO terms

Biological Process

No terms assigned in this category.

Molecular Function

GO:0032266 phosphatidylinositol-3-phosphate binding
GO:0043130 ubiquitin binding

Cellular Component

No terms assigned in this category.

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.
Pfam
PROSITE profiles