Vps36 is a subunit of ESCRT-II, a protein complex 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 transmembraneproteins 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. ESCRT (endosomal sorting complex required for transport)-I, -II and -III complexes are critical for MVB budding and sorting ofmonoubiquitinated cargo into the luminal vesicles []. Various Ub-binding domains(UBDs), such as UIM, UEV and NZF are found in suchmachineries [, ].The Vps 36 subunit of the ESCRT-II trafficking complex binds bothphosphoinositides and ubiquitin. All members of the Vps36 family contain adivergent GRAM/PH-like domain; yeast and some other fungi have one or twoNZF domains inserted in the GRAM/PH-like domain [, ].
This family includes Snf8 and Vps36. Vps36 is involved in Golgi to endosome trafficking. Snf8 is a component of the endosomal sorting complex required for transport II (ESCRT-II), which is required for multivesicular body (MVB) formation and sorting of endosomal cargo proteins into MVBs [].
Vps36 is a subunit of ESCRT-II, a protein complex 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 transmembraneproteins 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 ofmonoubiquitinated cargo into the luminal vesicles. Various Ub-binding domains(UBDs), such as UIM, UEV and NZF are found in suchmachineries. The Vps 36 subunit of the ESCRT-II trafficking complex binds bothphosphoinositides and ubiquitin. All members of the Vps36 family contain adivergent 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-containingmembranes, ubiquitin, and ESCRT-I. Like other known ubiquitin-binding domains,the GLUE domain interacts with the hydrophobic surface patch of ubiquitin. TheGLUE domain is the first ubiquitin-binding domain shown to bindphosphoinositides, and the ability of the same domain to bind both ubiquitinand 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 andone long alpha helix. The two sheets (beta1-beta4 and beta5-beta7) form a beta barrel-like structure, the C-terminal alpha helix is wedgedbetween 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 adifferent lipid binding pocket [, ].
