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Intrinsic Disorder at Genomic Scale: Genome-Wide Analysis of Intrinsic Disorder and Its Implication in Specific Protein Functional Classes in Arabidopsis Thaliana

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Intrinsic Disorder at Genomic Scale: Genome-Wide Analysis of Intrinsic Disorder and Its Implication in Specific Protein Functional Classes in Arabidopsis Thaliana ! ABSTRACT Protein functional features extracted from primary sequences: a focus on disordered regions. by Natalia Pietrosemoli In! this! thesis! we! implement! an! ensemble! of! sequence! analysis! strategies! aimed!at!identifying!functional!and!structural!protein!features.!The!first!part!of!this! work! was! dedicated! to! two! case! studies! of! specific! proteins! analyzed! to! provide! candidate! functional! positions! for! experimental! validation:! the! protein! alphaP synuclein!(αsyn)!and!the!alanine!racemases!protein!family.!In!the!case!of!αsyn,!the! objective! was! to! predict! its! aggregation! prone! regions.! For! the! alanine! racemase! protein!family,!the!scope!was!to!predict!sites!responsible!for!substrate!specificity.!In! these! two! studies,! computational! predictions! allowed! systematically! exploring! potentially!functionally!relevant!protein!sites!in!an!efficient!manner!that!may!not!be! possible! to! implement! with! traditional! experimental! approaches.! ! Our! strategy! provided!a!powerful!forecasting!tool!for!the!selection!of!candidate!sites!to!be!later! verified!experimentally.! In! the! second! part,! we! analyze! the! role! of! intrinsic! disorder! (ID)! as! a! modulator!of!protein!function!in!different!organisms!and!cellular!processes,!which! is! largely! unexplored.! As! key! components! of! the! diverse! cellular! pathways,! disordered! proteins! are! often! involved! in! many! diseases,! including! cancer! and! ( III!( ! neurodegenerative!diseases.!Thus,!there!is!an!impeding!need!to!unveil!the!general! principles!underlying!the!role!of!ID!in!proteins.!We!provide!a!multiPscale!analysis!of! the! involvement! of! ID! in! protein! function! starting! with! a! largePscale! analysis! at! genomic!level!of!the!role!of!ID!in!Arabidopsis,!zooming!in!into!the!specific!processes! of!vesicular!trafficking!in!Human!and!yeast,!and!finally!focusing!on!specific!proteins! of!diverse!organisms.!! The! results! of! this! thesis! provide! a! better! understanding! of! the! functional! roles! mediated! by! ID! in! different! organisms! and! biological! processes,! such! as! acting! as! flexible! linkers! connecting! structured! domains,! mediating! proteinPprotein! interactions,!and!assisting!the!quick!assembly!of!large!macromolecular!complexes.! In! addition,! we! present! evidence! of! the! use! of! ID! as! a! mechanism! to! increase! the! complexity! of! protein! and! biological! networks,! and! as! a! means! to! increase! the! adaptability! of! proteins! in! specific! processes.! ! Thus,! our! results! contribute! to! elucidating! the! relationship! between! network! and! organismal! complexity! and! ID,! while!they!also!provide!evidence!of!the!evolutionary!advantages!offered!by!ID.! ! ! Acknowledgements I! am! lucky! to! say! that! I! have! received! support! and! encouragement! from! a! great!number!of!people!during!these!last!years.!The!completion!of!my!dissertation! has!not!only!been!a!very!long!journey,!but!quite!a!bumpy!road!too.!! I! would! like! to! give! special! thanks! to! my! Thesis! CoPdirector,! Dr.! Florencio! Pazos,!head!of!the!Computational!Systems!Biology!Group!at!the!National!Centre!for! Biotechnology! (CNBPCSIC),! for! giving! me! the! opportunity! of! developing! this! dissertation!under!his!guidance.!He!was!full!of!invaluable!suggestions!and!insightful! comments,!and!it!was!truly!a!pleasure!to!work!with!him.! I!would!also!like!to!thank!my!Thesis!CoPdirector!Dr.!Laura!Segatori,!head!of! the! Cell! and! Protein! Engineering! Laboratory! at! Rice! University,! not! only! for! her! excellent! academic! guidance,! but! also! for! her! constant! encouragement! and! great! advice!along!all!these!years.!Thanks!for!pushing!me!! I!also!thank!other!members!of!my!dissertation!committee:!Dr.!Jianpeng!Ma! and!Dr.!Igoshin!for!their!time!and!constructive!feedback.!I!want!to!thank!Dr.!Rebecca! RichardsPKortum,! Chair! of! the! Department! of! Bioengineering! for! her! trust! and! support,!and!to!the!Department!Coordinator,!Gayle!Schroeder!for!her!constant!help! during!my!time!abroad.! My! most! sincere! gratitude! goes! to! Prof.! Alfonso! Valencia,! Director! of! the! Structural! Computational! Biology! and! Biocomputing! Programme! at! the! Spanish! ( V((! ! National!Cancer!Research!Centre!(CNIO),!for!giving!me!the!privilege!of!joining!his! group!as!a!visiting!scholar!and!for!his!willingness!to!help!in!difficult!times.!! All! my! collaborators! should! also! be! thanked! for! the! many! interesting! discussions!and!for!making!possible!a!good!part!of!my!research:!Dr.!Roberto!Solano,! head!of!the!The!jasmonate!signalling!pathway!in!Arabidopsis!Group!at!the!CNB,!Juan! Antonio! Garcia,! from! the! Department! of! Plant! Molecular! Genetics! at! the! CNB,! Dr.! Peter!Tompa,!Chair!of!the!Department!of!Structural!Biology!at!the!Vrije!Universiteit! Brussel,!and!Dr.!Felipe!Cava!and!Akbar!Espaillat!from!the!Department!of!Virology! and! Microbiology! at! the! Severo! Ochoa! Molecular! Biology! Center! (CBMSOPCSIC).! I! feel! very! lucky! for! having! had! the! opportunity! to! work! with! people! with! such! a! broad!spectrum!of!expertise.!! I! would! like! to! thank! the! members! of! the! Computational! Systems! Biology! Group!and!the!Bioinformatics!Initiative!at!the!CNB:!Mónica,!Toño,!Dany,!David!O.,! Juan! Carlos! O.,! Juan! Carlos! S.! and! David! SL.! Closely! working! with! such! brilliant! people!has!been!a!very!inspiring!intellectual!experience.!!My!thanks!also!go!to!all!the! members!of!my!former!Structural!Computational!Biology!Group!in!the!CNIO.!I’ll!take! with!me!great!knowledge!and!invaluable!memories!of!those!times.! !My!love!and!gratefulness!goes!to!all!my!family,!especially!to!my!wonderful! parents!and!brother!for!all!their!love,!patience!and!all!kinds!of!support.!Thanks!to! my!granma,!because!she!has!always!managed!to!transmit!to!me!all!her!encouraging! ! ( VI((! ! words,! tenaciousness! and! good! vibes,! wherever! and! whenever! I! need! them! the! most.!Granma,!you!truly!rock.! To!the!rest!of!my!big,!big!extended!family!of!friends,!past!and!present,!you! know!you!all!contributed!to!this!project!in!your!own!way,!thank!you!!To!my!friend! Chela,!because.! To! my! big! love! Antonio,! no! words! can! express! my! gratitude! for! your! unconditional!support!during!these!years.!All!I!know!is!that!if!we!could!survive!not! one,!but!two!of!these!“bumpy!roads”!together,!we!can!do!anything.!We!are!a!team!! Above!all,!I!thank!the!Universe!for!offering!me!this!wonderful!opportunity!to! undertake!this!venture!and!enabling!me!to!its!completion.!! ! ! ! Contents ABSTRACT'...................................................................................................................'II! ACKNOWLEDGEMENTS'...............................................................................................'IV! CONTENTS'.................................................................................................................'VII! LIST'OF'FIGURES'........................................................................................................'XII! LIST'OF'TABLES'.........................................................................................................'XIX! NOMENCLATURE'.......................................................................................................'XX! INTRODUCTION'...........................................................................................................'1! OBJECTIVES'.................................................................................................................'6! CHAPTER'1'..................................................................................................................'9! BACKGROUND'.............................................................................................................'9! 1.1.!COMPUTATIONAL!PREDICTION!OF!FUNCTIONAL!REGIONS!IN!PROTEINS!................................!10! 1.1.1.#Prediction#of#functional#sites#.........................................................................#11! 1.1.2.#Protein#sequence#alignments#and#functional#sites#........................................#13! 1.1.3.#Structure8based#methods#..............................................................................#20! 1.2.!PROTEIN!DISORDER,!NOT!SO!MESSY!AFTER!ALL!................................................................!21! 1.2.1.#Structural#and#functional#classification#of#protein#disorder#..........................#25! 1.2.2.#Protein#disorder#from#an#evolutionary#perspective#.......................................#30! 1.2.3.#What’s#all#the#fuzz#about#disorder?#...............................................................#33! 1.2.4.#Methods#to#predict#and#evaluate#protein#disorder#........................................#37! ( VIII!( ! 1.2.5.#Protein#disorder,#disease,#and#drug#development#.........................................#47! CHAPTER'2'................................................................................................................'51! 2.1.!INTRODUCTION!.........................................................................................................!51! 2.2.!ALPHA!SYNUCLEIN!AGGREGATION:!PREDICTING!THE!SEQUENCE<STRUCTURE!RELATIONSHIP!USING! RATIONAL!DESIGN!..........................................................................................................................!52! 2.2.1.#Hypothesis#.....................................................................................................#53! 2.2.2.#Methods#........................................................................................................#54!
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