A B-box 2 surface patch important for TRIM5alpha self-association, capsid binding avidity, and retrovirus restriction.
TRIM5alpha is a tripartite motif (TRIM) protein that consists of RING, B-box 2, coiled-coil, and B30.2(SPRY) domains. The TRIM5alpha(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 TRIM5alpha(rh) B-box 2 domain have been associated with alterations in TRIM5alpha(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 TRIM5alpha(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 TRIM5alpha(rh) half-life or the formation of cytoplasmic bodies. Thus, promoting cooperative TRIM5alpha(rh) interactions with the HIV-1 capsid represents a major mechanism whereby the B-box 2 domain potentiates HIV-1 restriction.
Diaz-Griffero
Felipe
F
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Qin
Xu-rong
XR
Hayashi
Fumiaki
F
Kigawa
Takanori
T
Finzi
Andres
A
Sarnak
Zoe
Z
Lienlaf
Maritza
M
Yokoyama
Shigeyuki
S
Sodroski
Joseph
J
D000818:Animals; D002213:Capsid / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012190:Retroviridae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D044767:Ubiquitin-Protein Ligases
D011506:Proteins; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases