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Elife. 2016 Jun 2;5. pii: e16309. doi: 10.7554/eLife.16309.

Mechanism of B-box 2 domain-mediated higher-order assembly of the retroviral restriction factor TRIM5α.

Author information

1
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States.
2
Department of Biochemistry, University of Utah, Salt Lake City, United States.
3
The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheeva, Israel.
4
Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheeva, Israel.

Abstract

Restriction factors and pattern recognition receptors are important components of intrinsic cellular defenses against viral infection. Mammalian TRIM5α proteins are restriction factors and receptors that target the capsid cores of retroviruses and activate ubiquitin-dependent antiviral responses upon capsid recognition. Here, we report crystallographic and functional studies of the TRIM5α B-box 2 domain, which mediates higher-order assembly of TRIM5 proteins. The B-box can form both dimers and trimers, and the trimers can link multiple TRIM5α proteins into a hexagonal net that matches the lattice arrangement of capsid subunits and enables avid capsid binding. Two modes of conformational flexibility allow TRIM5α to accommodate the variable curvature of retroviral capsids. B-box mediated interactions also modulate TRIM5α's E3 ubiquitin ligase activity, by stereochemically restricting how the N-terminal RING domain can dimerize. Overall, these studies define important molecular details of cellular recognition of retroviruses, and how recognition links to downstream processes to disable the virus.

KEYWORDS:

HIV; biochemistry; biophysics; higher-order assembly; protein structure; restriction factor; rhesus macaque; structural biology

PMID:
27253059
PMCID:
PMC4936894
DOI:
10.7554/eLife.16309
[Indexed for MEDLINE]
Free PMC Article

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