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PDBsum entry 4htw
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Viral protein
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PDB id
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4htw
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References listed in PDB file
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Key reference
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Title
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Gain-Of-Sensitivity mutations in a trim5-Resistant primary isolate of pathogenic siv identify two independent conserved determinants of trim5α specificity.
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Authors
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K.R.Mccarthy,
A.G.Schmidt,
A.Kirmaier,
A.L.Wyand,
R.M.Newman,
W.E.Johnson.
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Ref.
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Plos Pathog, 2013,
9,
e1003352.
[DOI no: ]
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PubMed id
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Abstract
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Retroviral capsid recognition by Trim5 blocks productive infection. Rhesus
macaques harbor three functionally distinct Trim5 alleles: Trim5α(Q) ,
Trim5α(TFP) and Trim5(CypA) . Despite the high degree of amino acid identity
between Trim5α(Q) and Trim5α(TFP) alleles, the Q/TFP polymorphism results in
the differential restriction of some primate lentiviruses, suggesting these
alleles differ in how they engage these capsids. Simian immunodeficiency virus
of rhesus macaques (SIVmac) evolved to resist all three alleles. Thus, SIVmac
provides a unique opportunity to study a virus in the context of the Trim5
repertoire that drove its evolution in vivo. We exploited the evolved rhesus
Trim5α resistance of this capsid to identify gain-of-sensitivity mutations that
distinguish targets between the Trim5α(Q) and Trim5α(TFP) alleles. While both
alleles recognize the capsid surface, Trim5α(Q) and Trim5α(TFP) alleles
differed in their ability to restrict a panel of capsid chimeras and single
amino acid substitutions. When mapped onto the structure of the SIVmac239 capsid
N-terminal domain, single amino acid substitutions affecting both alleles mapped
to the β-hairpin. Given that none of the substitutions affected Trim5α(Q)
alone, and the fact that the β-hairpin is conserved among retroviral capsids,
we propose that the β-hairpin is a molecular pattern widely exploited by
Trim5α proteins. Mutations specifically affecting rhesus Trim5α(TFP) (without
affecting Trim5α(Q) ) surround a site of conservation unique to primate
lentiviruses, overlapping the CPSF6 binding site. We believe targeting this site
is an evolutionary innovation driven specifically by the emergence of primate
lentiviruses in Africa during the last 12 million years. This modularity in
targeting may be a general feature of Trim5 evolution, permitting different
regions of the PRYSPRY domain to evolve independent interactions with capsid.
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