Mutations in or near the Transmembrane Domain Alter PMEL Amyloid Formation from Functional to Pathogenic 英文参考文献.docVIP

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Mutations in or near the Transmembrane Domain Alter PMEL Amyloid Formation from Functional to Pathogenic 英文参考文献.doc

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Mutations in or near the Transmembrane Domain Alter PMEL Amyloid Formation from Functional to Pathogenic 英文参考文献

MutationsinorneartheTransmembraneDomainAlter PMELAmyloidFormationfromFunctionaltoPathogenic BrendaWatt1,2,Danie`leTenza3,4,MarkA.Lemmon5,SusanneKerje6,Grac?aRaposo3,4,LeifAndersson6,7 MichaelS.Marks1,2 , * 1Department ofPathologyandLaboratory MedicineandDepartment ofPhysiology,UniversityofPennsylvania, Philadelphia,Pennsylvania, UnitedStatesofAmerica, 2CellandMolecularBiologyGraduateGroup,UniversityofPennsylvania,Philadelphia,Pennsylvania,UnitedStatesofAmerica,3InstitutCurie,CentredeRecherche,Paris, France,4CNRS,UMR-144,Paris,France,5DepartmentofBiochemistryandBiophysics,UniversityofPennsylvania,Philadelphia,Pennsylvania,UnitedStatesofAmerica, 6Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden, 7Department of Animal Breeding and Genetics,SwedishUniversityofAgriculturalSciences,Uppsala,Sweden Abstract PMELisapigmentcell-specificproteinthatformsphysiologicalamyloidfibrilsuponwhichmelaninsultimatelydepositin thelumenofthepigmentorganelle,themelanosome.WhereashypomorphicPMELmutationsinseveralspeciesresultina mildpigmentdilutionthatisinheritedinarecessivemanner,PMELallelesfoundintheDominantwhite(DW)chickenand Silverhorse(HoSi)—whichbearmutationsthatalterthePMELtransmembranedomain(TMD)andthatarethusoutsidethe amyloidcore—areassociatedwithastrikinglossofpigmentationthatisinheritedinadominantfashion.Hereweshowthat the DW and HoSi mutations alter PMEL TMD oligomerization and/or association with membranes, with consequent formation of aberrantly packed fibrils. The aberrant fibrils are associated with a loss of pigmentation in cultured melanocytes,suggestingthattheyinhibitmelaninproductionand/ormelanosomeintegrity.Asecondarymutationinthe Smoky chicken, which reverts the dominant DW phenotype, prevents the accumulation of PMEL in fibrillogenic compartmentsandthusavertsDW–associatedpigmentloss;asecondarymutationfoundintheDunchickenlikelydampens aHoSi–likedominantmutationinasimilarmanner.WeproposethattheD