| Type: | Domain | Name: | Vacuolar protein sorting protein 36, GLUE domain |
| 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 []. The multivesicular body (MVB) protein-sorting pathway targets transmembrane proteins either for degradation or for function in the vacuole/lysosomes. Thesignal for entry into this pathway is monoubiquitination of protein cargo, which results in incorporation of cargo into luminal vesicles at lateendosomes. Another crucial player is phosphatidylinositol 3-phosphate (PtdINS(3)P), which is enriched on early endosomes and on the luminal vesiclesof 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 bothphosphoinositides and ubiquitin. All members of the Vps36 family contain a divergent GRAM/PH-like domain and yeast and some other fungi have one or twoNZF 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 ESCRTmachinery, 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 bindphosphoinositides, and the ability of the same domain to bind both ubiquitin and a phosphoinositide opens interesting possibilities for coordination ofmembrane interactions and cargo recognition [, , , , ].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 GLUEdomain binds PtdIns3P via a positively charged lipid binding pocket, delineated by the variable loops beta1/beta2, beta5/beta6 and beta7/alpha1, incontrast to the vast majority of characterised PH domains, which use a different lipid binding pocket [, ]. | Short Name: | GLUE_dom |
