A B-Box 2 Surface Patch Important for TRIM5{alpha} Self-Association, Capsid Binding Avidity, and Retrovirus Restriction

doi:10.1128/JVI.01307-09

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Journal of Virology, October 2009, p. 10737-10751, Vol. 83, No. 20
0022-538X/09/$08.00+0 doi:10.1128/JVI.01307-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A B-Box 2 Surface Patch Important for TRIM5 ${alpha}$ Self-Association, Capsid Binding Avidity, and Retrovirus Restriction ^,

Felipe Diaz-Griffero,¹ Xu-rong Qin,³ Fumiaki Hayashi,³ Takanori Kigawa,³^,4 Andres Finzi,¹ Zoe Sarnak,¹ Maritza Lienlaf,¹ Shigeyuki Yokoyama,³^,5 and Joseph Sodroski¹^,2^*

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115,¹ Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115,² Systems and Structural Biology Center, Yokohama Institute, Riken, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0445, Japan,³ Department of Computational Intelligence and Systems Science, Interdisciplinary Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8550, Japan,⁴ Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, 2-11-16 yayoi, Bunko-Ku, Tokyo 113-0032, Japan⁵

Received 25 June 2009/ Accepted 29 July 2009

TRIM5 ${alpha}$ is a tripartite motif (TRIM) protein that consists ofRING, B-box 2, coiled-coil, and B30.2(SPRY) domains. The TRIM5 ${alpha}$ _rhprotein from rhesus monkeys recognizes the human immunodeficiencyvirus type 1 (HIV-1) capsid as it enters the host cell and blocksvirus infection prior to reverse transcription. HIV-1-restrictingability can be eliminated by disruption of the B-box 2 domain.Changes in the TRIM5 ${alpha}$ _rh B-box 2 domain have been associated withalterations in TRIM5 ${alpha}$ _rh turnover, the formation of cytoplasmicbodies and higher-order oligomerization. We present here thenuclear magnetic resonance structure of the TRIM5 B-box 2 domainand identify an unusual hydrophobic patch (cluster 1) on thedomain surface. Alteration of cluster 1 or the flanking arginine121 resulted in various degrees of inactivation of HIV-1 restriction,in some cases depending on compensatory changes in other nearbycharged residues. For this panel of TRIM5 ${alpha}$ _rh B-box 2 mutants,inhibition of HIV-1 infection was strongly correlated with higher-orderself-association and binding affinity for capsid complexes butnot with TRIM5 ${alpha}$ _rh half-life or the formation of cytoplasmic bodies.Thus, promoting cooperative TRIM5 ${alpha}$ _rh interactions with the HIV-1capsid represents a major mechanism whereby the B-box 2 domainpotentiates HIV-1 restriction.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney Street-CLSB 1010, Boston, MA 02115. Phone: (617) 632-3371. Fax: (671) 632-4338. E-mail: joseph_sodroski{at}dfci.harvard.edu

Published ahead of print on 5 August 2009.

Supplemental material for this article may be found at http://jvi.asm.org/.

A B-Box 2 Surface Patch Important for TRIM5 Self-Association, Capsid Binding Avidity, and Retrovirus Restriction ,

A B-Box 2 Surface Patch Important for TRIM5 ${alpha}$ Self-Association, Capsid Binding Avidity, and Retrovirus Restriction ^,