Release of autoinhibition converts ESCRT-III components into potent inhibitors of HIV-1 budding

Zamborlini, Alessia; Usami, Yoshiko; Radoshitzky, Sheli R.; Попова, Е. Н.; Palù, Giorgio; Göttlinger, Heinrich G.

doi:10.1073/pnas.0603788103

Cited by 164 publications

(223 citation statements)

References 45 publications

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“…Like the CHMP4 subunits, the CHMP1-3 subunits of ESCRT-III also have C-terminal amphipathic helices [MIT interacting motifs (MIM)], but in these cases the helices bind the MIT domains of VPS4, Vta1p/ LIP5, and AMSH and thereby recruit ATPase and deubiquitylating activities to the membrane (43)(44)(45)(46)(47)(48). Hence, the terminal helices of different ESCRT-III subunits must display distinct binding surfaces to ensure specificity in protein recruitment.…”

Section: Discussionmentioning

confidence: 99%

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ALIX-CHMP4 interactions in the human ESCRT pathway

McCullough

Fisher

Whitby

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

214

252

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The ESCRT pathway facilitates membrane fission events during enveloped virus budding, multivesicular body formation, and cytokinesis. To promote HIV budding and cytokinesis, the ALIX protein must bind and recruit CHMP4 subunits of the ESCRT-III complex, which in turn participate in essential membrane remodeling functions. Here, we report that the Bro1 domain of ALIX binds specifically to C-terminal residues of the human CHMP4 proteins (CHMP4A-C). Crystal structures of the complexes reveal that the CHMP4 C-terminal peptides form amphipathic helices that bind across the conserved concave surface of ALIXBro1. ALIX-dependent HIV-1 budding is blocked by mutations in exposed ALIXBro1 residues that help contribute to the binding sites for three essential hydrophobic residues that are displayed on one side of the CHMP4 recognition helix (M/L/IxxLxxW). The homologous CHMP1-3 classes of ESCRT-III proteins also have C-terminal amphipathic helices, but, in those cases, the three hydrophobic residues are arrayed with L/I/MxxxLxxL spacing. Thus, the distinct patterns of hydrophobic residues provide a ''code'' that allows the different ESCRT-III subunits to bind different ESCRT pathway partners, with CHMP1-3 proteins binding MIT domain-containing proteins, such as VPS4 and Vta1/LIP5, and CHMP4 proteins binding Bro1 domaincontaining proteins, such as ALIX.cytokinesis ͉ ESCRT-III ͉ HIV ͉ mutivesicular body

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Section: Discussionmentioning

confidence: 99%

“…As shown in Fig. 1B, terminal fragments from all three CHMP4 proteins bound ALIX Bro1-V with similar affinities (44,48, and 41 M, respectively), demonstrating that all three CHMP4 proteins encode C-terminal ALIX binding sites. Similar binding data were also obtained for the shorter ALIX Bro1 construct (see Fig.…”

mentioning

confidence: 90%

ALIX-CHMP4 interactions in the human ESCRT pathway

McCullough

Fisher

Whitby

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

214

252

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“…1). The latter mediates both intramolecular inhibition of the ESCRT-III domain and intermolecular interaction with subunitspecific factors that regulate filament dynamics (Bajorek et al, 2009;Muziol et al, 2006;Stuchell-Brereton et al, 2007;Zamborlini et al, 2006). Deletion of the regulatory region converts ESCRT-III subunits into dominant-negative mutants that are able to block ESCRT-dependent processes such as the release of HIV-1 virions from infected cells .…”

Section: Introductionmentioning

confidence: 99%

CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines

Belly

Bodon

Blot

et al. 2010

Journal of Cell Science

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SummaryThe highly conserved ESCRT-III complex is responsible for deformation and cleavage of membranes during endosomal trafficking and other cellular activities. In humans, dominant mutations in the ESCRT-III subunit CHMP2B cause frontotemporal dementia (FTD). The decade-long process leading to this cortical degeneration is not well understood. One possibility is that, akin to other neurodegenerative diseases, the pathogenic protein affects the integrity of dendritic spines and synapses before any neuronal death. Using confocal microscopy and 3D reconstruction, we examined whether expressing the FTD-linked mutants CHMP2Bintron5 and CHMP2B 10 in cultured hippocampal neurons modified the number or structure of spines. Both mutants induced a significant decrease in the proportion of large spines with mushroom morphology, without overt degeneration. Furthermore, CHMP2B 10 induced a drop in frequency and amplitude of spontaneous excitatory postsynaptic currents, suggesting that the more potent synapses were lost. These effects seemed unrelated to changes in autophagy. Depletion of endogenous CHMP2B by RNAi resulted in morphological changes similar to those induced by mutant CHMP2B, consistent with dominant-negative activity of pathogenic mutants. Thus, CHMP2B is required for spine growth. Taken together, these results demonstrate that a mutant ESCRT-III subunit linked to a human neurodegenerative disease can disrupt the normal pattern of spine development.

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“…Structural studies of CHMP3 suggest that CHMP proteins have an autoinhibitory activity whereby the uncomplexed protein folds into a closed conformation through the attractive charges. However, following activation, the protein conformation may 'open', enabling CHMP proteins to associate with each other, forming a lattice on the membrane (Lata et al, 2008a;Muziol et al, 2006;Shim et al, 2007;Zamborlini et al, 2006). It has been proposed that the N-terminal basic region associates with the membrane via electrostatic charges with the lipid bilayer (Muziol et al, 2006), although additional anchorage may be provided by phosphoinositide-binding domains found in CHMP3 (Whitley et al, 2003) and CHMP4 (Lin et al, 2005) and a myristyl group in CHMP6 (Yorikawa et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

No strings attached: the ESCRT machinery in viral budding and cytokinesis

McDonald

Martín-Serrano

2009

Journal of Cell Science

103

104

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Since the initial discovery of the endosomal sorting complex required for transport (ESCRT) pathway, research in this field has exploded. ESCRT proteins are part of the endosomal trafficking system and play a crucial role in the biogenesis of multivesicular bodies by functioning in the formation of vesicles that bud away from the cytoplasm. Subsequently, a surprising role for ESCRT proteins was defined in the budding step of some enveloped retroviruses, including HIV-1. ESCRT proteins are also employed in this outward budding process, which results in the resolution of a membranous tether between the host cell and the budding virus particle. Remarkably, it has recently been described that ESCRT proteins also have a role in the topologically equivalent process of cell division. In the same way that viral particles recruit the ESCRT proteins to the site of viral budding, ESCRT proteins are also recruited to the midbody – the site of release of daughter cell from mother cell during cytokinesis. In this Commentary, we describe recent advances in the understanding of ESCRT proteins and how they act to mediate these diverse processes.

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Release of autoinhibition converts ESCRT-III components into potent inhibitors of HIV-1 budding

Cited by 164 publications

References 45 publications

ALIX-CHMP4 interactions in the human ESCRT pathway

ALIX-CHMP4 interactions in the human ESCRT pathway

CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines

No strings attached: the ESCRT machinery in viral budding and cytokinesis

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