title: Structural insights into the stabilization of the human immunodeficiency virus type 1 capsid protein by the cyclophilin-binding domain and implications on the virus cycle.
abstract: During infection, human immunodeficiency virus type 1 (HIV-1) interacts with the cellular host factor cyclophilin A (CypA) through residues 85-93 of the N-terminal domain of HIV-1's capsid protein (CA). The role of the CA:CypA interaction is still unclear. Previous studies showed that a CypA-binding loop mutant, Δ87-97, has increased ability to assemble in vitro. We used this mutant to infer whether the CypA-binding region has an overall effect on CA stability, as measured by pressure and chemical perturbation. We built a SAXS-based envelope model for the dimer of both WT and Δ87-97. A new conformational arrangement of the dimers is described, showing the structural plasticity that CA can adopt. In protein folding studies, the deletion of the loop drastically reduces CA stability, as assayed by high hydrostatic pressure and urea. We hypothesize that the deletion promotes a rearrangement of helix 4, which may enhance the heterotypic interaction between the N- and C-terminal domains of CA dimers. In addition, we propose that the cyclophilin-binding loop may modulate capsid assembly during infection, either in the cytoplasm or near the nucleus by binding to the nuclear protein Nup385.
authors.affiliation: Instituto de Bioquímica Médica, Instituto Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, Brazil. Electronic address: cortines@micro.ufrj.br.
authors.forename: Juliana R
authors.initials: JR
authors.lastname: Cortines
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro-UFRJ, Rio de Janeiro 21941-590, Brazil. Electronic address: mauricio@pharma.ufrj.br.
authors.forename: Luís Mauricio T R
authors.initials: LM
authors.lastname: Lima
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil. Electronic address: mohana@biof.ufrj.br.
authors.forename: Ronaldo
authors.initials: R
authors.lastname: Mohana-Borges
authors.affiliation: Instituto de Bioquímica Médica, Instituto Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, Brazil. Electronic address: thiagomillen@yahoo.com.br.
authors.forename: Thiago de A
authors.initials: Tde A
authors.lastname: Millen
authors.affiliation: Instituto de Bioquímica Médica, Instituto Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, Brazil. Electronic address: lgaspar@bio.fiocruz.br.
authors.forename: Luciane Pinto
authors.initials: LP
authors.lastname: Gaspar
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: jlanman@purdue.edu.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Lanman
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: prevelig@uab.edu.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Prevelige
authors.affiliation: Instituto de Bioquímica Médica, Instituto Nacional de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, Brazil. Electronic address: jerson@bioqmed.ufrj.br.
authors.forename: Jerson L
authors.initials: JL
authors.lastname: Silva
mesh_terms: D000595:Amino Acid Sequence; D036022:Capsid Proteins / Q000737:chemistry* / Q000378:metabolism*; D021984:Cyclophilin A / Q000378:metabolism*; D015497:HIV-1 / Q000737:chemistry* / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055550:Protein Stability; D053838:Scattering, Small Angle; D019065:Virus Assembly; D014961:X-Ray Diffraction
chemical_list: D036022:Capsid Proteins; D021984:Cyclophilin A
keywords: Capsid protein; Cyclophilin; High hydrostatic pressure; Human immunodeficiency virus; SAXS