Structural and biochemical studies of ALIX/AIP1 and its role in retrovirus budding.
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.
Fisher
Robert D
RD
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Chung
Hyo-Young
HY
Zhai
Qianting
Q
Robinson
Howard
H
Sundquist
Wesley I
WI
Hill
Christopher P
CP
D020816:Amino Acid Motifs; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D018360:Crystallography, X-Ray; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism; D015683:Gene Products, gag / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D004860:Infectious Anemia Virus, Equine / Q000737:chemistry / Q000254:growth & development / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000378:metabolism; D054301:gag Gene Products, Human Immunodeficiency Virus
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D015683:Gene Products, gag; D006023:Glycoproteins; C117020:PDCD6IP protein, human; D011993:Recombinant Fusion Proteins; D014759:Viral Envelope Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C083002:p6 gag protein, Human immunodeficiency virus 1