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

Zinaida Yudina; Amanda Roa; Rory Johnson; Nikolaos Biris; Daniel A. de Souza Aranha Vieira; Vladislav Tsiperson; Natalia Reszka; Alexander B. Taylor; P. John Hart; Borries Demeler; Felipe Diaz-Griffero; Dmitri N. Ivanov

doi:10.1016/j.celrep.2015.06.072

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

Zinaida Yudina
, Amanda Roa
, Rory Johnson
, Nikolaos Biris
, Daniel A. de Souza Aranha Vieira
, Vladislav Tsiperson
, Natalia Reszka
, Alexander B. Taylor
, P. John Hart
, Borries Demeler
, Felipe Diaz-Griffero
, Dmitri N. Ivanov

Chemistry and Biochemistry

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

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.

Original language	English
Pages (from-to)	788-797
Number of pages	10
Journal	Cell Reports
Volume	12
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2015.06.072
State	Published - Aug 4 2015

Funding

This research was supported in part by the Collaborative Development Award to D.N.I. from the Center for the Structural Biology of Cellular Host Elements in Egress, Trafficking, and Assembly of HIV (CHEETAH; NIH P50 GM082545 ); R01 AI087390 , R21 AI102824 , and R56 AI108432 to F.D.-G; Robert A. Welch Foundation grant AQ-1399 to P.J.H; NIH R01 AI104476 to D.N.I.; and Scholar Award from the Cancer Prevention and Research Institute of Texas (CPRIT) to D.N.I. A.R., D.A.d.S.A.V., V.T., N.R., and F.D.-G. were supported by NIH grants R01 AI087390 , R21 AI102824 , and R56 AI108432 to F.D.-G. The NMR, X-ray, and Analytical Ultracentrifugation core facilities at the UT Health Science Center at San Antonio (UTHSCSA) are supported in part by the NIH P30 CA054174 to the Cancer Therapy and Research Center. B.D. acknowledges support from NSF for the development of the UltraScan Science Gateway used in the analysis of AUC data ( ACI-1339649 and TG-MCB070039 ). X-ray diffraction data were collected at the Advanced Photon Source beamline 24-IDC NE-CAT funded by NIH-NIGMS P41 GM103403 and NIH-ORIP HEI S10 RR029205 at Argonne National Laboratory under DOE Office of Science contract no. DE-AC02-06CH11357 .

Funders	Funder number
P41 GM103403
ACI-1339649, TG-MCB070039
R00MH086162, R56AI108432, R01AI104476, P30CA054174, R01AI087390, R21AI102824
P50GM082545
AQ-1399, R01 AI104476
P30 CA054174
DE-AC02-06CH11357
Argonne National Laboratory
S10RR029205

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10.1016/j.celrep.2015.06.072

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@article{f60f218c0f994250ac837769ea2aa663,

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.",

author = "Zinaida Yudina and Amanda Roa and Rory Johnson and Nikolaos Biris and \{de Souza Aranha Vieira\}, \{Daniel A.\} and Vladislav Tsiperson and Natalia Reszka and Taylor, \{Alexander B.\} and Hart, \{P. John\} and Borries Demeler and Felipe Diaz-Griffero and Ivanov, \{Dmitri N.\}",

note = "Publisher Copyright: {\textcopyright} 2015 The Authors.",

year = "2015",

month = aug,

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doi = "10.1016/j.celrep.2015.06.072",

language = "English",

volume = "12",

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journal = "Cell Reports",

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T1 - RING Dimerization Links Higher-Order Assembly of TRIM5α to Synthesis of K63-Linked Polyubiquitin

AU - Yudina, Zinaida

AU - Roa, Amanda

AU - Johnson, Rory

AU - Biris, Nikolaos

AU - de Souza Aranha Vieira, Daniel A.

AU - Tsiperson, Vladislav

AU - Reszka, Natalia

AU - Taylor, Alexander B.

AU - Hart, P. John

AU - Demeler, Borries

AU - Diaz-Griffero, Felipe

AU - Ivanov, Dmitri N.

PY - 2015/8/4

Y1 - 2015/8/4

N2 - 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.

AB - 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.

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DO - 10.1016/j.celrep.2015.06.072

M3 - Article

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AN - SCOPUS:84938551576

SN - 2211-1247

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EP - 797

JO - Cell Reports

JF - Cell Reports

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ER -

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

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