title: Structural basis for viral late-domain binding to Alix.
abstract: The modular protein Alix is a central node in endosomal-lysosomal trafficking and the budding of human immunodeficiency virus (HIV)-1. The Gag p6 protein of HIV-1 contains a LYPx(n)LxxL motif that is required for Alix-mediated budding and binds a region of Alix spanning residues 360-702. The structure of this fragment of Alix has the shape of the letter 'V' and is termed the V domain. The V domain has a topologically complex arrangement of 11 alpha-helices, with connecting loops that cross three times between the two arms of the V. The conserved residue Phe676 is at the center of a large hydrophobic pocket and is crucial for binding to a peptide model of HIV-1 p6. Overexpression of the V domain inhibits HIV-1 release from cells. This inhibition of release is reversed by mutations that block binding of the Alix V domain to p6.
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), US Department of Health and Human Services, Bethesda, Maryland 20892, USA.
authors.forename: Sangho
authors.initials: S
authors.lastname: Lee
authors.forename: Anjali
authors.initials: A
authors.lastname: Joshi
authors.forename: Kunio
authors.initials: K
authors.lastname: Nagashima
authors.forename: Eric O
authors.initials: EO
authors.lastname: Freed
authors.forename: James H
authors.initials: JH
authors.lastname: Hurley
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D056827:Endosomal Sorting Complexes Required for Transport; D015683:Gene Products, gag / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology* / Q000648:ultrastructure; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010649:Phenylalanine; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D015683:Gene Products, gag; C117020:PDCD6IP protein, human; D054301:gag Gene Products, Human Immunodeficiency Virus; C083002:p6 gag protein, Human immunodeficiency virus 1; D010649:Phenylalanine