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Journal of Virology, October 2007, p. 10362-10378, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.00703-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Modulation of Retroviral Restriction and Proteasome Inhibitor-Resistant Turnover by Changes in the TRIM5{alpha} B-Box 2 Domain{triangledown}

Felipe Diaz-Griffero,1 Alak Kar,1 Michel Perron,1 Shi-Hua Xiang,1 Hassan Javanbakht,1 Xing Li,1 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 021152

Received 3 April 2007/ Accepted 2 July 2007

An intact B-box 2 domain is essential for the antiretroviral activity of TRIM5{alpha}. We modeled the structure of the B-box 2 domain of TRIM5{alpha} based on the existing three-dimensional structure of the B-box 2 domain of human TRIM29. Using this model, we altered the residues predicted to be exposed on the surface of this globular structure. Most of the alanine substitutions in these residues exerted little effect on the antiretroviral activity of human TRIM5{alpha}hu or rhesus monkey TRIM5{alpha}rh. However, alteration of arginine 119 of TRIM5{alpha}hu or the corresponding arginine 121 of TRIM5{alpha}rh diminished the abilities of the proteins to restrict retroviral infection without affecting trimerization or recognition of the viral capsid. The abilities of these functionally defective TRIM5{alpha} proteins to accelerate the uncoating of the targeted retroviral capsid were abolished. Removal of the positively charged side chain from B-box 2 arginines 119/120/121 resulted in diminished proteasome-independent turnover of TRIM5{alpha} and the related restriction factor TRIMCyp. However, testing of an array of mutants revealed that the rapid turnover and retroviral restriction functions of this B-box 2 region are separable.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney Street-JFB 824, Boston, MA 02115. Phone: (617) 632-3371. Fax: (671) 632-4338. E-mail: joseph_sodroski{at}dfci.harvard.edu

{triangledown} Published ahead of print on 11 July 2007.

Journal of Virology, October 2007, p. 10362-10378, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.00703-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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