title: Rhesus monkey TRIM5α SPRY domain recognizes multiple epitopes that span several capsid monomers on the surface of the HIV-1 mature viral core.
abstract: The restriction factor TRIM5α binds to the capsid protein of the retroviral core and blocks retroviral replication. The affinity of TRIM5α for the capsid is a major host tropism determinant of HIV and other primate immunodeficiency viruses, but the molecular interface involved in this host-pathogen interaction remains poorly characterized. Here we use NMR spectroscopy to investigate binding of the rhesus TRIM5α SPRY domain to a selection of HIV capsid constructs. The data are consistent with a model in which one SPRY domain interacts with more than one capsid monomer within the assembled retroviral core. The highly mobile SPRY v1 loop appears to span the gap between neighboring capsid hexamers making interhexamer contacts critical for restriction. The interaction interface is extensive, involves mobile loops and multiple epitopes, and lacks interaction hot spots. These properties, which may enhance resistance of TRIM5α to capsid mutations, result in relatively low affinity of the individual SPRY domains for the capsid, and the TRIM5α-mediated restriction depends on the avidity effect arising from the oligomerization of TRIM5α.
authors.affiliation: Department of Biochemistry and Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Biris
authors.forename: Andrei
authors.initials: A
authors.lastname: Tomashevski
authors.forename: Akash
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Felipe
authors.initials: F
authors.lastname: Diaz-Griffero
authors.forename: Dmitri N
authors.initials: DN
authors.lastname: Ivanov
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002213:Capsid / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases
chemical_list: D036022:Capsid Proteins; D000939:Epitopes; D011506:Proteins; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases
keywords: HIV; HSQC; NMR; SPRY; TRIM5α; TROSY; heteronuclear single quantum coherence; transverse relaxation optimized spectroscopy