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1、TheHepatitisEVirusPolyprolineRegionIsInvolvedinViralAdaptationMichaelA.Purdy*,JamesLara,YuryE.KhudyakovCentersforDiseaseControlandPrevention,NationalCenterforHIV/Hepatitis/STD/TBPrevention,DivisionofViralHepatitis,Atlanta,Georgia,UnitedStatesofAmericaAbstractGenomesofhepatitisEvirus(HEV),rub
2、ivirusandcutthroatvirus(CTV)containaregionofhighprolinedensityandlowaminoacid(aa)complexity,namedthepolyprolineregion(PPR).InHEVgenotypes1,3and4,itistheonlyregionwithinthenon-structuralopenreadingframe(ORF1)withpositiveselection(410codonswithdN/dS.1).Thisregionhasthehighestdensityofsiteswith
3、homoplasyvalues.0.5.Genotypes3and4show,3-foldincreaseinhomoplasticdensity(HD)inthePPRcomparedtoanyotherregioninORF1,genotype1doesnotexhibitsignificantHD(p,0.0001).PPRsequencedivergencewasfoundtobe2-foldgreaterforHEVgenotypes3and4thanforgenotype1.ThedatasuggestthePPRplaysanimportantroleinhost
4、-rangeadaptation.AlthoughthePPRappearstobehypervariableandhomoplastic,itretainsasmuchphylogeneticsignalasanyothersimilarsizedregionintheORF1,indicatingthatconvergentevolutionoperateswithinthemajorHEVphylogeneticlineages.Analysesofsequence-basedsecondarystructureandthetertiarystructureidentif
5、yPPRasanintrinsicallydisorderedregion(IDR),implicatingitsroleinregulationofreplication.Theidentifiedpropensityforthedisorder-to-orderstatetransitionsindicatesthePPRisinvolvedinprotein-proteininteractions.Furthermore,thePPRofallfourHEVgenotypescontainssevenputativelinearbindingmotifsforligand
6、sinvolvedintheregulationofawidenumberofcellularsignalingprocesses.Structure-basedanalysisofpossiblemolecularfunctionsofthesemotifsshowedthePPRispronetobindawidevarietyofligands.Collectively,thesedatasuggestaroleforthePPRinHEVadaptation.ParticularlyasanIDR,thePPRlikelycontributestofinetuningo
7、fviralreplicationthroughprotein-proteininteractionsandshouldbeconsideredasatargetfordevelopmentofnovelanti-viraldrugs.Citation:PurdyMA,LaraJ,KhudyakovYE(2012)TheHepatitisEVirusPolyprolineRegionIsInvolvedinViralAdaptation.PLoSONE7(4):e35974.doi:10.1
