Knowing Your ESCRT

R e s e a r ch highlights

Nature Reviews Molecular Cell Biology | AOP, published online 17 October 2007; doi:10.1038/nrm2288

m e m b rane t raffic k ing Knowing your ESCRT

DOI: The multiprotein ESCRT (endo- subunit Did2 and in the mammalian When Williams and colleagues 10.1038/nrm2288 somal sorting complex required for ESCRT-III subunits CHMP1A and determined the crystal structure of the transport) complexes are required for CHMP2A. Mutation of MIM in MIT domain of an archaeal ATPase, membrane fission events, including Vps2 or Did2 caused sorting defects; they found that it closely resembled endosomal intralumenal vesicle a protein that normally sorts to the that of Vps4. It also interacted with formation and viral budding. The vacuolar lumen accumulated in an archaeal ESCRT-III-like protein, VPS4 AAA-family ATPase binds the vacuolar membrane instead. even though archaea do not have an ...the ESCRT- to membrane-bound ESCRT-III In a separate study, Sundquist endomembrane system. This suggests complexes and catalyses their and co-workers showed that the MIT that the ESCRT-III–Vps4 association III–Vps4 disassembly, which may be coupled domains of human proteins VPS4A may reflect an ancient function that association to membrane fission and vesicle and VPS4B bind the C termini predates the divergence of eukaryotes may reflect formation. Two reports now provide of human ESCRT-III proteins and archaea. a structural basis for the interaction CHMP1–3, albeit with varying MIT mutations that inhibit an ancient between VPS4 and ESCRT-III. affinity. Both groups determined CHMP1A binding caused defective function that Williams and colleagues showed structures of complexes between the endosomal protein sorting into predates the that the C-terminal region of yeast MIT domain of Vps4/VPS4A and the vacuolar lumen, blocked VPS4 divergence of ESCRT-III protein Vps2 is sufficient the C termini of ESCRT-III proteins recruitment to mammalian endo- for binding the MIT (microtubule- (Vps2 and CHMP1A, respectively), somes and relieved dominant-negative eukaryotes interacting and transport) domain of and the structures are in good VPS4 inhibition of viral budding. So, and archaea. Vps4. The six Vps2 residues that form agreement. The MIT domain forms the recognition of membrane-associ- the MIT-interacting motif (MIM) are a three-helix bundle of antiparallel ated ESCRT-III by VPS4 ATPase, and also present in the yeast ESCRT-III helices, whereas the longer MIM- subsequent ATP hydrolysis, is crucial containing region of Vps2 comprises for ESCRT-III function. Sundquist three short helical segments (the and colleagues suggest that membrane shorter CHMP1A construct com- association of ESCRT-III may serve prises only the third helix). The third to expose the C-terminal regions helix of Vps2/CHMP1A binds in the of CHMP1–3, which promotes the groove between helices 2 and 3 of recruitment of oligomeric VPS4. It is MIT, but in an opposite orientation not yet clear how ATP hydrolysis leads to that of a canonical tetratrico to the disassembly of the ESCRT-III peptide-like repeat interaction complex and to vesicle formation. — thereby creating a unique inter Arianne Heinrichs action mode. Distinct hydrophobic ORIGINAL RESEARCH PAPERS Obita, T. pockets along the groove bind three et al. Structural basis for selective recognition of conserved Leu/hydrophobic residues ESCRT-III by the AAA ATPase Vps4. Nature 11 Oct in the MIM of Vps2/CHMP1A and 2007 (doi:10.1038/nature06171) | Stuchell- Brereton, M. D. et al. ESCRT-III recognition by flanking residues make important VPS4 ATPases. Nature 11 Oct 2007 (doi:10.1038/ salt-bridging interactions. nature06172) Lawrence Keogh Further Reading Williams, R. L. & Urbe, S. The emerging shape of the ESCRT machinery. Nature Rev. Mol. Cell Biol. 8, 355–368 (2007)