TY - JOUR
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.
N1 - Funding Information:
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 .
Publisher Copyright:
© 2015 The Authors.
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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U2 - 10.1016/j.celrep.2015.06.072
DO - 10.1016/j.celrep.2015.06.072
M3 - Article
C2 - 26212332
AN - SCOPUS:84938551576
SN - 2211-1247
VL - 12
SP - 788
EP - 797
JO - Cell Reports
JF - Cell Reports
IS - 5
ER -