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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:
; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
Contributing Org.:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
OSTI Identifier:
1242423
Alternate Identifier(s):
OSTI ID: 1208690
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article: Published Article
Journal Name:
Cell Reports
Additional Journal Information:
Journal Name: Cell Reports Journal Volume: 12 Journal Issue: 5; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
Netherlands
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Yudina, Zinaida, Roa, Amanda, Johnson, Rory, Biris, Nikolaos, de Souza Aranha Vieira, Daniel A., Tsiperson, Vladislav, Reszka, Natalia, Taylor, Alexander B., Hart, P. John, Demeler, Borries, Diaz-Griffero, Felipe, and Ivanov, Dmitri N. RING Dimerization Links Higher-Order Assembly of TRIM5α to Synthesis of K63-Linked Polyubiquitin. Netherlands: N. p., 2015. Web. doi:10.1016/j.celrep.2015.06.072.
Yudina, Zinaida, Roa, Amanda, Johnson, Rory, Biris, Nikolaos, de Souza Aranha Vieira, Daniel A., Tsiperson, Vladislav, Reszka, Natalia, Taylor, Alexander B., Hart, P. John, Demeler, Borries, Diaz-Griffero, Felipe, & Ivanov, Dmitri N. RING Dimerization Links Higher-Order Assembly of TRIM5α to Synthesis of K63-Linked Polyubiquitin. Netherlands. https://doi.org/10.1016/j.celrep.2015.06.072
Yudina, Zinaida, Roa, Amanda, Johnson, Rory, Biris, Nikolaos, de Souza Aranha Vieira, Daniel A., Tsiperson, Vladislav, Reszka, Natalia, Taylor, Alexander B., Hart, P. John, Demeler, Borries, Diaz-Griffero, Felipe, and Ivanov, Dmitri N. 2015. "RING Dimerization Links Higher-Order Assembly of TRIM5α to Synthesis of K63-Linked Polyubiquitin". Netherlands. https://doi.org/10.1016/j.celrep.2015.06.072.
@article{osti_1242423,
title = {RING Dimerization Links Higher-Order Assembly of TRIM5α to Synthesis of K63-Linked Polyubiquitin},
author = {Yudina, Zinaida and Roa, Amanda and Johnson, Rory and Biris, Nikolaos and de Souza Aranha Vieira, Daniel A. and Tsiperson, Vladislav and Reszka, Natalia and Taylor, Alexander B. and Hart, P. John and Demeler, Borries and Diaz-Griffero, Felipe and Ivanov, Dmitri N.},
abstractNote = {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.},
doi = {10.1016/j.celrep.2015.06.072},
url = {https://www.osti.gov/biblio/1242423}, journal = {Cell Reports},
issn = {2211-1247},
number = 5,
volume = 12,
place = {Netherlands},
year = {Sat Aug 01 00:00:00 EDT 2015},
month = {Sat Aug 01 00:00:00 EDT 2015}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at https://doi.org/10.1016/j.celrep.2015.06.072

Citation Metrics:
Cited by: 63 works
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Works referenced in this record:

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


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


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


Biochemical and Biophysical Characterization of a Chimeric TRIM21-TRIM5α Protein
journal, September 2008


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


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