title: Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity.
abstract: TRIMCyps are anti-retroviral proteins that have arisen independently in New World and Old World primates. All TRIMCyps comprise a CypA domain fused to the tripartite domains of TRIM5alpha but they have distinct lentiviral specificities, conferring HIV-1 restriction in New World owl monkeys and HIV-2 restriction in Old World rhesus macaques. Here we provide evidence that Asian macaque TRIMCyps have acquired changes that switch restriction specificity between different lentiviral lineages, resulting in species-specific alleles that target different viruses. Structural, thermodynamic and viral restriction analysis suggests that a single mutation in the Cyp domain, R69H, occurred early in macaque TRIMCyp evolution, expanding restriction specificity to the lentiviral lineages found in African green monkeys, sooty mangabeys and chimpanzees. Subsequent mutations have enhanced restriction to particular viruses but at the cost of broad specificity. We reveal how specificity is altered by a scaffold mutation, E143K, that modifies surface electrostatics and propagates conformational changes into the active site. Our results suggest that lentiviruses may have been important pathogens in Asian macaques despite the fact that there are no reported lentiviral infections in current macaque populations.
authors.affiliation: University College London Medical Research Council Centre for Medical Molecular Virology, London, UK.
authors.forename: Laura M J
authors.initials: LM
authors.lastname: Ylinen
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Price
authors.forename: Jane
authors.initials: J
authors.lastname: Rasaiyaah
authors.forename: Stéphane
authors.initials: S
authors.lastname: Hué
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rose
authors.forename: Flavia
authors.initials: F
authors.lastname: Marzetta
authors.forename: Leo C
authors.initials: LC
authors.lastname: James
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Towers
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D021984:Cyclophilin A / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D015658:HIV Infections / Q000235:genetics*; D016180:Lentivirus Infections / Q000235:genetics; D008251:Macaca / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D050506:Mutant Chimeric Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010802:Phylogeny; D020836:Protein Structure, Quaternary; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D044767:Ubiquitin-Protein Ligases
chemical_list: D050506:Mutant Chimeric Proteins; D011506:Proteins; C526560:TRIM5-cyclophilin A protein, Macaca nemestrina; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases; D021984:Cyclophilin A
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