期刊
JOURNAL OF VIROLOGY
卷 83, 期 20, 页码 10737-10751出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01307-09
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资金
- National Institutes of Health [1K99MH086162-01]
- American Foundation for AIDS Research Mathilde Krim [106987-43-RFHF]
- Dana-Farber Cancer Institute
- Riken Structural Genomics/Proteomics Initiative of the National Project on Protein Structural and Functional Analyses, Ministry of Education, Culture, Sports, Science, and Technology of Japan
- [K99/R00]
TRIM5 alpha is a tripartite motif (TRIM) protein that consists of RING, B-box 2, coiled-coil, and B30.2(SPRY) domains. The TRIM5 alpha(rh) protein from rhesus monkeys recognizes the human immunodeficiency virus type 1 (HIV-1) capsid as it enters the host cell and blocks virus infection prior to reverse transcription. HIV-1-restricting ability can be eliminated by disruption of the B-box 2 domain. Changes in the TRIM5 alpha(rh) B-box 2 domain have been associated with alterations in TRIM5 alpha(rh) turnover, the formation of cytoplasmic bodies and higher-order oligomerization. We present here the nuclear magnetic resonance structure of the TRIM5 B-box 2 domain and identify an unusual hydrophobic patch (cluster 1) on the domain surface. Alteration of cluster 1 or the flanking arginine 121 resulted in various degrees of inactivation of HIV-1 restriction, in some cases depending on compensatory changes in other nearby charged residues. For this panel of TRIM5 alpha(rh) B-box 2 mutants, inhibition of HIV-1 infection was strongly correlated with higher-order self-association and binding affinity for capsid complexes but not with TRIM5 alpha(rh) half-life or the formation of cytoplasmic bodies. Thus, promoting cooperative TRIM5 alpha(rh) interactions with the HIV-1 capsid represents a major mechanism whereby the B-box 2 domain potentiates HIV-1 restriction.
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