title: Mechanism of B-box 2 domain-mediated higher-order assembly of the retroviral restriction factor TRIM5α.
abstract: Restriction factors and pattern recognition receptors are important components of intrinsic cellular defenses against viral infection. Mammalian TRIM5α proteins are restriction factors and receptors that target the capsid cores of retroviruses and activate ubiquitin-dependent antiviral responses upon capsid recognition. Here, we report crystallographic and functional studies of the TRIM5α B-box 2 domain, which mediates higher-order assembly of TRIM5 proteins. The B-box can form both dimers and trimers, and the trimers can link multiple TRIM5α proteins into a hexagonal net that matches the lattice arrangement of capsid subunits and enables avid capsid binding. Two modes of conformational flexibility allow TRIM5α to accommodate the variable curvature of retroviral capsids. B-box mediated interactions also modulate TRIM5α's E3 ubiquitin ligase activity, by stereochemically restricting how the N-terminal RING domain can dimerize. Overall, these studies define important molecular details of cellular recognition of retroviruses, and how recognition links to downstream processes to disable the virus.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Wagner
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States.
authors.forename: Marcin D
authors.initials: MD
authors.lastname: Roganowicz
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Skorupka
authors.affiliation: Department of Biochemistry, University of Utah, Salt Lake City, United States.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Alam
authors.affiliation: Department of Biochemistry, University of Utah, Salt Lake City, United States.
authors.forename: Devin
authors.initials: D
authors.lastname: Christensen
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States.
authors.forename: Ginna
authors.initials: G
authors.lastname: Doss
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States.
authors.forename: Yueping
authors.initials: Y
authors.lastname: Wan
authors.affiliation: The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheeva, Israel.|Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheeva, Israel.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Frank
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States.
authors.forename: Barbie K
authors.initials: BK
authors.lastname: Ganser-Pornillos
authors.affiliation: Department of Biochemistry, University of Utah, Salt Lake City, United States.
authors.forename: Wesley I
authors.identifier: 0000-0001-9988-6021
authors.initials: WI
authors.lastname: Sundquist
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States.
authors.forename: Owen
authors.identifier: 0000-0001-9056-5002
authors.initials: O
authors.lastname: Pornillos
mesh_terms: D000818:Animals; D002213:Capsid / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D008253:Macaca mulatta; D008958:Models, Molecular; D011487:Protein Conformation; D000072417:Protein Domains; D055503:Protein Multimerization; D012190:Retroviridae / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D025801:Ubiquitin
keywords: HIV; biochemistry; biophysics; higher-order assembly; protein structure; restriction factor; rhesus macaque; structural biology