title: CPSF6 defines a conserved capsid interface that modulates HIV-1 replication.
abstract: The HIV-1 genome enters cells inside a shell comprised of capsid (CA) protein. Variation in CA sequence alters HIV-1 infectivity and escape from host restriction factors. However, apart from the Cyclophilin A-binding loop, CA has no known interfaces with which to interact with cellular cofactors. Here we describe a novel protein-protein interface in the N-terminal domain of HIV-1 CA, determined by X-ray crystallography, which mediates both viral restriction and host cofactor dependence. The interface is highly conserved across lentiviruses and is accessible in the context of a hexameric lattice. Mutation of the interface prevents binding to and restriction by CPSF6-358, a truncated cytosolic form of the RNA processing factor, cleavage and polyadenylation specific factor 6 (CPSF6). Furthermore, mutations that prevent CPSF6 binding also relieve dependence on nuclear entry cofactors TNPO3 and RanBP2. These results suggest that the HIV-1 capsid mediates direct host cofactor interactions to facilitate viral infection.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Cambridge, United Kingdom.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Price
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Fletcher
authors.forename: Torsten
authors.initials: T
authors.lastname: Schaller
authors.forename: Tom
authors.initials: T
authors.lastname: Elliott
authors.forename: KyeongEun
authors.initials: K
authors.lastname: Lee
authors.forename: Vineet N
authors.initials: VN
authors.lastname: KewalRamani
authors.forename: Jason W
authors.initials: JW
authors.lastname: Chin
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Towers
authors.forename: Leo C
authors.initials: LC
authors.lastname: James
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000378:metabolism; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000378:metabolism; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000378:metabolism; D011485:Protein Binding; D016415:Sequence Alignment; D053586:Virus Internalization; D014779:Virus Replication; D028961:beta Karyopherins / Q000378:metabolism; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D036022:Capsid Proteins; D007211:Indoles; D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; C000591221:PF-3450074; C546476:TNPO3 protein, human; D028961:beta Karyopherins; C450562:cleavage factor Im, human; D039221:mRNA Cleavage and Polyadenylation Factors; C094493:ran-binding protein 2; D010649:Phenylalanine