Aggregation Propensity of the Human Proteome 英文参考文献.docVIP

AggregationPropensityoftheHumanProteome ElodieMonsellier1.,MatteoRamazzotti1.,Niccolo` Taddei1,FabrizioChiti1,2* 1DipartimentodiScienzeBiochimiche,Universita`deglistudidiFirenze,Florence,Italy,2Consorziointeruniversitrio‘‘IstitutoNazionaleBiostruttureeBiosistemi’’(I.N.B.B.), Rome,Italy Abstract Formationofamyloid-likefibrilsisinvolvedinnumeroushumanproteindepositiondiseases,butisalsoanintrinsicproperty of polypeptide chains in general. Progress achieved recently now allows the aggregation propensity of proteins to be analyzedoverlargescales.Inthisworkweusedapreviouslydevelopedpredictivealgorithmtoanalyzethepropensityof the34,180proteinsequencesofthehumanproteometoformamyloid-likefibrils. Weshowthatlongproteins have,on average,lessintenseaggregationpeaksthanshortones.Humanproteinsinvolvedinproteindepositiondiseasesdonot differextensivelyfromtherestoftheproteome,furtherdemonstratingthegeneralityofproteinaggregation.Wewerealso abletoreproducesomeoftheresultsobtainedwithotheralgorithms,demonstratingthattheydonotdependonthetype ofcomputationaltoolemployed.Forexample,proteinswithdifferentsubcellularlocalizationswerefoundtohavedifferent aggregation propensities, in relation to the various efficiencies of quality control mechanisms. Membrane proteins, intrinsicallydisorderedproteins,andfoldedproteinswereconfirmedtohaveverydifferentaggregationpropensities,asa consequence of their different structures and cellular microenvironments. In addition, gatekeeper residues at strategic positions of the sequences were found to protect human proteins from aggregation. The results of these comparative analyseshighlighttheexistenceofintimatelinksbetweenthepropensityofproteinstoformaggregateswithb-structure andtheirbiology.Inparticular,theyemphasizetheexistenceofanegativeselectionpressurethatfinelymodulatesprotein sequencesinordertoadapttheiraggregationpropensitytotheirbiologicalcontext. Citation:MonsellierE,RamazzottiM,TaddeiN,ChitiF(2008)AggregationPropensityoftheHumanProteo