Abstract
ALIX/AIP1 functions in enveloped virus budding, endosomal protein sorting, and many other cellular processes. Retroviruses, including HIV-1, SIV, and EIAV, bind and recruit ALIX through YPX(n)L late-domain motifs (X = any residue; n = 1-3). Crystal structures reveal that human ALIX is composed of an N-terminal Bro1 domain and a central domain that is composed of two extended three-helix bundles that form elongated arms that fold back into a "V." The structures also reveal conformational flexibility in the arms that suggests that the V domain may act as a flexible hinge in response to ligand binding. YPX(n)L late domains bind in a conserved hydrophobic pocket on the second arm near the apex of the V, whereas CHMP4/ESCRT-III proteins bind a conserved hydrophobic patch on the Bro1 domain, and both interactions are required for virus budding. ALIX therefore serves as a flexible, extended scaffold that connects retroviral Gag proteins to ESCRT-III and other cellular-budding machinery.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Motifs
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Calcium-Binding Proteins / chemistry*
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Calcium-Binding Proteins / metabolism*
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Carrier Proteins / chemistry*
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Carrier Proteins / metabolism*
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Cell Cycle Proteins / chemistry*
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Cell Cycle Proteins / metabolism*
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Cell Line
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Crystallography, X-Ray
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Endosomal Sorting Complexes Required for Transport
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Endosomes / metabolism
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Gene Products, gag / metabolism
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Glycoproteins / metabolism
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HIV-1 / chemistry
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HIV-1 / drug effects
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HIV-1 / growth & development
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HIV-1 / metabolism*
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HeLa Cells
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Humans
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Infectious Anemia Virus, Equine / chemistry
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Infectious Anemia Virus, Equine / growth & development
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Infectious Anemia Virus, Equine / metabolism*
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Models, Molecular
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Mutation
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Viral Envelope Proteins / metabolism
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gag Gene Products, Human Immunodeficiency Virus
Substances
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Calcium-Binding Proteins
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Carrier Proteins
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Cell Cycle Proteins
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Endosomal Sorting Complexes Required for Transport
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Gene Products, gag
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Glycoproteins
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PDCD6IP protein, human
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Recombinant Fusion Proteins
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Viral Envelope Proteins
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gag Gene Products, Human Immunodeficiency Virus
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p6 gag protein, Human immunodeficiency virus 1