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3.A.31.  The Endosomal Sorting Complexes Required for Transport III (ESCRT-III) Family 

The endosomal sorting complexes required for transport (ESCRTs) catalyze reverse-topological scission from the inner face of membrane necks in HIV budding, multivesicular endosome biogenesis, cytokinesis, and other pathways. Schöneberg et al. 2018 encapsulated ESCRT-III subunits Snf7, Vps24, and Vps2 and the AAA+ ATPase (adenosine triphosphatase) Vps4 in giant vesicles from which membrane nanotubes reflecting the correct topology of scission could be pulled. Upon ATP release by photo-uncaging, this system generates forces within the nanotubes that leads to membrane scission in a manner dependent upon Vps4 catalytic activity and Vps4 coupling to the ESCRT-III proteins. Imaging of scission revealed Snf7 and Vps4 puncta within nanotubes whose presence followed ATP release, correlated with force generation and nanotube constriction, and preceded scission. These observations directly verify long-standing predictions that ATP-hydrolyzing assemblies of ESCRT-III and Vps4 sever membranes (Schöneberg et al. 2018).

The ESCRT III complex consists of at least 18 proteins a is required for the sorting and concentration of proteins resulting in the entry of these proteins into the invaginating vesicles of the multivesicular body (Babst et al. 2002). The sequential action of ESCRT-0, -I, and -II together with the ordered assembly of ESCRT-III links membrane invagination to cargo sorting. Membrane scission in the neck of the growing vesicle releases mature, cargo-laden vesicles into the lumen (Buchkovich et al. 2013, Adell et al. 2014). ESCRT-III is critical for late steps in MVB sorting, such as membrane invagination and final cargo sorting and recruitment of late-acting components of the sorting machinery (Adell et al. 2014). SNF7 is the most abundant ESCRT-III subunit which forms membrane-sculpting filaments with 30 Å periodicity and a exposed cationic membrane-binding surface (Tang et al. 2015). Its activation requires a prominent conformational rearrangement to expose protein-membrane and protein-protein interfaces. SNF7 filaments then form spirals that may function as spiral springs (Chiaruttini et al. 2015). The elastic expansion of compressed SNF7 spirals generates an area difference between the two sides of the membrane and thus curvature, which could be the origin of membrane deformation leading eventually to fission. SNF7 recruits BRO1, which in turn recruits DOA4, which deubiquitinates cargos before their enclosure within MVB vesicles (Amerik et al. 2000, Kim et al. 2005). ESCRT-III is also recruited to the nuclear envelope (NE) by integral INM proteins to surveil and clear defective nuclear pore complex (NPC) assembly intermediates to ensure the fidelity of NPC assembly (Webster et al. 2014).Vsp4 is an ATPase that provides the force generation and membrane scission by ESCRT-III (Schöneberg et al. 2018).

As noted above, the sorting of transmembrane proteins (e.g., cell surface receptors) into the multivesicular body (MVB) pathway to the lysosomal/vacuolar lumen requires the function of the ESCRT protein complexes. The soluble coiled-coil-containing proteins Vps2, Vps20, Vps24, and Snf7 are recruited from the cytoplasm to endosomal membranes where they oligomerize into a protein complex, ESCRT-III. ESCRT-III contains two functionally distinct subcomplexes. The Vps20-Snf7 subcomplex binds to the endosomal membrane, in part via the myristoyl group of Vps20. The Vps2-Vps24 subcomplex binds to the Vps20-Snf7 complex and thereby serves to recruit additional cofactors to this site of protein sorting. Evidence for a role for ESCRT-III in sorting and/or concentration of MVB cargoes has been forthcoming (Schöneberg et al. 2018 encapsulated ESCRT-III subunits Snf7, Vps24, and Vps2 and the AAA+ ATPase (adenosine triphosphatase) Vps4 in giant vesicles from which membrane nanotubes reflecting the correct topology of scission could be pulled. Upon ATP release by photo-uncaging, this system generates forces within the nanotubes that leads to membrane scission in a manner dependent upon Vps4 catalytic activity and Vps4 coupling to the ESCRT-III proteins. Imaging of scission revealed Snf7 and Vps4 puncta within nanotubes whose presence followed ATP release, correlated with force generation and nanotube constriction, and preceded scission. These observations directly verify long-standing predictions that ATP-hydrolyzing assemblies of ESCRT-III and Vps4 sever membranes (Schöneberg et al. 2018).

The ESCRT III complex consists of at least 18 proteins a is required for the sorting and concentration of proteins resulting in the entry of these proteins into the invaginating vesicles of the multivesicular body (Babst et al. 2002). The sequential action of ESCRT-0, -I, and -II together with the ordered assembly of ESCRT-III links membrane invagination to cargo sorting. Membrane scission in the neck of the growing vesicle releases mature, cargo-laden vesicles into the lumen (Buchkovich et al. 2013, Adell et al. 2014). ESCRT-III is critical for late steps in MVB sorting, such as membrane invagination and final cargo sorting and recruitment of late-acting components of the sorting machinery (Adell et al. 2014). SNF7 is the most abundant ESCRT-III subunit which forms membrane-sculpting filaments with 30 Å periodicity and a exposed cationic membrane-binding surface (Tang et al. 2015). Its activation requires a prominent conformational rearrangement to expose protein-membrane and protein-protein interfaces. SNF7 filaments then form spirals that may function as spiral springs (Chiaruttini et al. 2015). The elastic expansion of compressed SNF7 spirals generates an area difference between the two sides of the membrane and thus curvature, which could be the origin of membrane deformation leading eventually to fission. SNF7 recruits BRO1, which in turn recruits DOA4, which deubiquitinates cargos before their enclosure within MVB vesicles (Amerik et al. 2000, Kim et al. 2005). ESCRT-III is also recruited to the nuclear envelope (NE) by integral INM proteins to surveil and clear defective nuclear pore complex (NPC) assembly intermediates to ensure the fidelity of NPC assembly (Webster et al. 2014).Vsp4 is an ATPase that provides the force generation and membrane scission by ESCRT-III (Schöneberg et al. 2018).

As noted above, the sorting of transmembrane proteins (e.g., cell surface receptors) into the multivesicular body (MVB) pathway to the lysosomal/vacuolar lumen requires the function of the ESCRT protein complexes. The soluble coiled-coil-containing proteins Vps2, Vps20, Vps24, and Snf7 are recruited from the cytoplasm to endosomal membranes where they oligomerize into a protein complex, ESCRT-III. ESCRT-III contains two functionally distinct subcomplexes. The Vps20-Snf7 subcomplex binds to the endosomal membrane, in part via the myristoyl group of Vps20. The Vps2-Vps24 subcomplex binds to the Vps20-Snf7 complex and thereby serves to recruit additional cofactors to this site of protein sorting. Evidence for a role for ESCRT-III in sorting and/or concentration of MVB cargoes has been forthcoming (Schöneberg et al. 2018).

The ESCRT III complex consists of at least 18 proteins a is required for the sorting and concentration of proteins resulting in the entry of these proteins into the invaginating vesicles of the multivesicular body (Babst et al. 2002). The sequential action of ESCRT-0, -I, and -II together with the ordered assembly of ESCRT-III links membrane invagination to cargo sorting. Membrane scission in the neck of the growing vesicle releases mature, cargo-laden vesicles into the lumen (Buchkovich et al. 2013, Adell et al. 2014). ESCRT-III is critical for late steps in MVB sorting, such as membrane invagination and final cargo sorting and recruitment of late-acting components of the sorting machinery (Adell et al. 2014). SNF7 is the most abundant ESCRT-III subunit which forms membrane-sculpting filaments with 30 Å periodicity and a exposed cationic membrane-binding surface (Tang et al. 2015). Its activation requires a prominent conformational rearrangement to expose protein-membrane and protein-protein interfaces. SNF7 filaments then form spirals that may function as spiral springs (Chiaruttini et al. 2015). The elastic expansion of compressed SNF7 spirals generates an area difference between the two sides of the membrane and thus curvature, which could be the origin of membrane deformation leading eventually to fission. SNF7 recruits BRO1, which in turn recruits DOA4, which deubiquitinates cargos before their enclosure within MVB vesicles (Amerik et al. 2000, Kim et al. 2005). ESCRT-III is also recruited to the nuclear envelope (NE) by integral INM proteins to surveil and clear defective nuclear pore complex (NPC) assembly intermediates to ensure the fidelity of NPC assembly (Webster et al. 2014).Vsp4 is an ATPase that provides the force generation and membrane scission by ESCRT-III (Schöneberg et al. 2018).

As noted above, the sorting of transmembrane proteins (e.g., cell surface receptors) into the multivesicular body (MVB) pathway to the lysosomal/vacuolar lumen requires the function of the ESCRT protein complexes. The soluble coiled-coil-containing proteins Vps2, Vps20, Vps24, and Snf7 are recruited from the cytoplasm to endosomal membranes where they oligomerize into a protein complex, ESCRT-III. ESCRT-III contains two functionally distinct subcomplexes. The Vps20-Snf7 subcomplex binds to the endosomal membrane, in part via the myristoyl group of Vps20. The Vps2-Vps24 subcomplex binds to the Vps20-Snf7 complex and thereby serves to recruit additional cofactors to this site of protein sorting. Evidence for a role for ESCRT-III in sorting and/or concentration of MVB cargoes has been forthcoming (Babst et al. 2002).

This family belongs to the: AAA-ATPase Superfamily.

References associated with 3.A.31 family:

Adell, M.A., G.F. Vogel, M. Pakdel, M. Müller, H. Lindner, M.W. Hess, and D. Teis. (2014). Coordinated binding of Vps4 to ESCRT-III drives membrane neck constriction during MVB vesicle formation. J. Cell Biol. 205: 33-49. 24711499
Amerik, A.Y., J. Nowak, S. Swaminathan, and M. Hochstrasser. (2000). The Doa4 deubiquitinating enzyme is functionally linked to the vacuolar protein-sorting and endocytic pathways. Mol. Biol. Cell 11: 3365-3380. 11029042
Babst, M., D.J. Katzmann, E.J. Estepa-Sabal, T. Meerloo, and S.D. Emr. (2002). Escrt-III: an endosome-associated heterooligomeric protein complex required for mvb sorting. Dev Cell 3: 271-282. 12194857
Buchkovich, N.J., W.M. Henne, S. Tang, and S.D. Emr. (2013). Essential N-terminal insertion motif anchors the ESCRT-III filament during MVB vesicle formation. Dev Cell 27: 201-214. 24139821
Chiaruttini, N., L. Redondo-Morata, A. Colom, F. Humbert, M. Lenz, S. Scheuring, and A. Roux. (2015). Relaxation of Loaded ESCRT-III Spiral Springs Drives Membrane Deformation. Cell 163: 866-879. 26522593
Diehn, T.A., M.D. Bienert, B. Pommerrenig, Z. Liu, C. Spitzer, N. Bernhardt, J. Fuge, A. Bieber, N. Richet, F. Chaumont, and G.P. Bienert. (2019). Boron demanding tissues of Brassica napus express specific sets of functional Nodulin26-like Intrinsic Proteins and BOR1 transporters. Plant J. [Epub: Ahead of Print] 31148338
Hoban, K., S.Y. Lux, J. Poprawski, Y. Zhang, J. Shepherdson, P.G. Castiñeira, S. Pesari, T. Yao, D.C. Prosser, C. Norris, and B. Wendland. (2020). ESCRT-dependent protein sorting is required for the viability of yeast clathrin-mediated endocytosis mutants. Traffic. [Epub: Ahead of Print] 32255230
Kim, J., S. Sitaraman, A. Hierro, B.M. Beach, G. Odorizzi, and J.H. Hurley. (2005). Structural basis for endosomal targeting by the Bro1 domain. Dev Cell 8: 937-947. 15935782
Schöneberg, J., M.R. Pavlin, S. Yan, M. Righini, I.H. Lee, L.A. Carlson, A.H. Bahrami, D.H. Goldman, X. Ren, G. Hummer, C. Bustamante, and J.H. Hurley. (2018). ATP-dependent force generation and membrane scission by ESCRT-III and Vps4. Science 362: 1423-1428. 30573630
Tang, S., W.M. Henne, P.P. Borbat, N.J. Buchkovich, J.H. Freed, Y. Mao, J.C. Fromme, and S.D. Emr. (2015). Structural basis for activation, assembly and membrane binding of ESCRT-III Snf7 filaments. Elife 4:. 26670543
Webster, B.M., P. Colombi, J. Jäger, and C.P. Lusk. (2014). Surveillance of nuclear pore complex assembly by ESCRT-III/Vps4. Cell 159: 388-401. 25303532