title: RING Dimerization Links Higher-Order Assembly of TRIM5α to Synthesis of K63-Linked Polyubiquitin.
abstract: Members of the tripartite motif (TRIM) protein family of RING E3 ubiquitin (Ub) ligases promote innate immune responses by catalyzing synthesis of polyubiquitin chains linked through lysine 63 (K63). Here, we investigate the mechanism by which the TRIM5α retroviral restriction factor activates Ubc13, the K63-linkage-specific E2. Structural, biochemical, and functional characterization of the TRIM5α:Ubc13-Ub interactions reveals that activation of the Ubc13-Ub conjugate requires dimerization of the TRIM5α RING domain. Our data explain how higher-order oligomerization of TRIM5α, which is promoted by the interaction with the retroviral capsid, enhances the E3 Ub ligase activity of TRIM5α and contributes to its antiretroviral function. This E3 mechanism, in which RING dimerization is transient and depends on the interaction of the TRIM protein with the ligand, is likely to be conserved in many members of the TRIM family and may have evolved to facilitate recognition of repetitive epitope patterns associated with infection.
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Zinaida
authors.initials: Z
authors.lastname: Yudina
authors.affiliation: Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Roa
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Rory
authors.initials: R
authors.lastname: Johnson
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Biris
authors.affiliation: Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: de Souza Aranha Vieira
authors.affiliation: Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Tsiperson
authors.affiliation: Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Reszka
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA; X-ray Crystallography Core Laboratory, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Taylor
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA; X-ray Crystallography Core Laboratory, University of Texas Health Science Center, San Antonio, TX 78229, USA; Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs, South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
authors.forename: P John
authors.initials: PJ
authors.lastname: Hart
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Borries
authors.initials: B
authors.lastname: Demeler
authors.affiliation: Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: felipe.diaz-griffero@einstein.yu.edu.
authors.forename: Felipe
authors.initials: F
authors.lastname: Diaz-Griffero
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA. Electronic address: ivanov@uthscsa.edu.
authors.forename: Dmitri N
authors.initials: DN
authors.lastname: Ivanov
mesh_terms: D000818:Animals; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004285:Dogs; D025821:Polyubiquitin / Q000096:biosynthesis* / Q000235:genetics; D055503:Protein Multimerization / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; D014764:Viral Proteins; D025821:Polyubiquitin; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases