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Title: RING Dimerization Links Higher-Order Assembly of TRIM5α to Synthesis of K63-Linked Polyubiquitin

Journal Article · · Cell Reports

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Contributing Organization:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1242423
Alternate ID(s):
OSTI ID: 1208690
Journal Information:
Cell Reports, Journal Name: Cell Reports Vol. 12 Journal Issue: 5; ISSN 2211-1247
Publisher:
ElsevierCopyright Statement
Country of Publication:
Netherlands
Language:
English
Citation Metrics:
Cited by: 63 works
Citation information provided by
Web of Science

References (49)

Structural rearrangements in the membrane penetration protein of a non-enveloped virus journal August 2004
TRIM5α selectively binds a restriction-sensitive retroviral capsid journal June 2005
The B30.2(SPRY) Domain of the Retroviral Restriction Factor TRIM5α Exhibits Lineage-Specific Length and Sequence Variation in Primates journal May 2005
Reconstitution of the RIG-I Pathway Reveals a Signaling Role of Unanchored Polyubiquitin Chains in Innate Immunity journal April 2010
Structure of the rhesus monkey TRIM5  PRYSPRY domain, the HIV capsid recognition module journal July 2012
Clustal W and Clustal X version 2.0 journal September 2007
Proteasomal Degradation of TRIM5α during Retrovirus Restriction journal May 2008
Requirements for capsid-binding and an effector function in TRIMCyp-mediated restriction of HIV-1 journal August 2006
Biochemical Characterization of a Recombinant TRIM5α Protein That Restricts Human Immunodeficiency Virus Type 1 Replication journal September 2008
The tripartite motif coiled-coil is an elongated antiparallel hairpin dimer journal February 2014
Structural studies of postentry restriction factors reveal antiparallel dimers that enable avid binding to the HIV-1 capsid lattice journal June 2014
Proteasome Inhibition Reveals that a Functional Preintegration Complex Intermediate Can Be Generated during Restriction by Diverse TRIM5 Proteins journal October 2006
Genomic analysis of the TRIM family reveals two groups of genes with distinct evolutionary properties journal January 2008
Modulation of Retroviral Restriction and Proteasome Inhibitor-Resistant Turnover by Changes in the TRIM5α B-Box 2 Domain journal July 2007
All Three Variable Regions of the TRIM5α B30.2 Domain Can Contribute to the Specificity of Retrovirus Restriction journal September 2006
RING Domain Mutations Uncouple TRIM5  Restriction of HIV-1 from Inhibition of Reverse Transcription and Acceleration of Uncoating journal November 2011
Biochemical and Biophysical Characterization of a Chimeric TRIM21-TRIM5α Protein journal September 2008
Role of TRIM5  RING Domain E3 Ubiquitin Ligase Activity in Capsid Disassembly, Reverse Transcription Blockade, and Restriction of Simian Immunodeficiency Virus journal June 2011
Quantitative analysis of in vitro ubiquitinated cyclin B1 reveals complex chain topology journal June 2006
BIRC7–E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer journal August 2012
Structural Symmetry and Protein Function journal June 2000
E2 interaction and dimerization in the crystal structure of TRAF6 journal May 2009
WebLogo: A Sequence Logo Generator journal May 2004
Hexagonal assembly of a restricting TRIM5  protein journal December 2010
Contribution of RING domain to retrovirus restriction by TRIM5α depends on combination of host and virus journal April 2010
Contribution of E3-Ubiquitin Ligase Activity to HIV-1 Restriction by TRIM5 rh: Structure of the RING Domain of TRIM5  journal July 2011
The TRIM5α B-Box 2 Domain Promotes Cooperative Binding to the Retroviral Capsid by Mediating Higher-Order Self-Association journal September 2008
Restriction of Human Immunodeficiency Virus Type 1 by TRIM-CypA Occurs with Rapid Kinetics and Independently of Cytoplasmic Bodies, Ubiquitin, and Proteasome Activity journal December 2005
A human TRIM5α B30.2/SPRY domain mutant gains the ability to restrict and prematurely uncoat B-tropic murine leukemia virus journal September 2008
Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5  restriction factor journal March 2006
Rapid turnover and polyubiquitylation of the retroviral restriction factor TRIM5 journal June 2006
A B-Box 2 Surface Patch Important for TRIM5α Self-Association, Capsid Binding Avidity, and Retrovirus Restriction journal August 2009
Ubiquitin Transfer from the E2 Perspective: Why is UbcH5 So Promiscuous? journal December 2006
Molecular Insights into the Function of RING Finger (RNF)-containing Proteins hRNF8 and hRNF168 in Ubc13/Mms2-dependent Ubiquitylation journal May 2012
Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21 journal March 2013
TRIM5 is an innate immune sensor for the retrovirus capsid lattice journal April 2011
Monte Carlo analysis of sedimentation experiments journal June 2007
TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity journal March 2007
A protein engagement RING journal September 2012
The cytoplasmic body component TRIM5α restricts HIV-1 infection in Old World monkeys journal February 2004
RING-type E3 ligases: Master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination journal January 2014
Mms2–Ubc13 covalently bound to ubiquitin reveals the structural basis of linkage-specific polyubiquitin chain formation journal September 2006
The human and African green monkey TRIM5  genes encode Ref1 and Lv1 retroviral restriction factor activities journal July 2004
Structure of an E3:E2∼Ub Complex Reveals an Allosteric Mechanism Shared among RING/U-box Ligases journal September 2012
Parsimonious regularization using genetic algorithms applied to the analysis of analytical ultracentrifugation experiments conference July 2007
Tripartite-motif proteins and innate immune regulation journal February 2011
Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis journal July 2012
Proteasome inhibitors uncouple rhesus TRIM5  restriction of HIV-1 reverse transcription and infection journal April 2006
Caging the Beast: TRIM5α Binding to the HIV-1 Core journal April 2011

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