RNA-protein interac/ons and the structure of the gene/c code · RNA-protein interac/ons and the...
Transcript of RNA-protein interac/ons and the structure of the gene/c code · RNA-protein interac/ons and the...
RNA-proteininterac/onsandthestructureofthegene/ccode
BojanZagrovicDepartmentofStructuralandComputa/onalBiology
UniversityofVienna
Evolu/onworkshop,Salzburg,07.07.2018
Physicochemicalcomplementarityoneofthemostpowerfulparadigmsinbiology
geneduplica/on
PDB:1QPH
immuneresponse
an#body
an#genPDB:1WBU
enzyma/ccatalysis
Krautetal.PLOSB,4,2006
anovelcomplementarity?
messengerRNA-proteinrela/onship:thecornerstoneofmolecularbiology
S21mRNA
ribosomalproteinS21(PDB:4GD2)
linkedbytheuniversalgene/ccode
physicochemicalconnec/on?
Whatistheaffinityofaminoacidsforpyrimidines?
pyridine
LEUinDMP:H2O
ASPinDMP:H2O
WoeseCRetal.,PNAS,55:966-974(1966)MathewDC&Luthey-SchultenZ,JMolEvol,66:519-528(2008)
pyrimidine
CarlWoese
*DMP:2,6-dimethylpyridine
a.u.
THECENTRALFINDING
HlevnjakM,PolyanskyAA&ZagrovicB,NucleicAcidsResearch,40,2012PolyanskyAA,HlevnjakM&ZagrovicB,RNABiology,10,2013
H.sapiens
*
*
Asta/s/callyrobustfindingofuniversalvalidity
HlevnjakM,PolyanskyAA&ZagrovicB,NucleicAcidsResearch,40,2012PolyanskyAA,HlevnjakM&ZagrovicB,RNABiology,10,2013
gene#ccodeshuffling differentorganisms
Whataboutnaturalbasesand,inpar/cular,purines?
• 3Dstructuresof~300protein-RNAcomplexes
freeenergyproxiesfromcontactsta#s#cs:
*inunitsofkBT
PolyanskyAA&ZagrovicB,NAR,18:8434-8443(2013)
medianR-valuesforprofilematchingdistribuaons
mRNAPUR-densityvs.proteinG-affinity
mR
NA
PU
R-d
ensi
ty
prot
ein
G-a
ffini
ty (k
T)
mR
NA
PY
R-d
ensi
ty
prot
ein
PY
R-a
ffini
ty (k
T)
mRNAPYR-densityvs.proteinPYR-affinity
Animportantexcep/on:ADE-preferringaminoacidstendtobeencodedbyPYR-richstretchesandviceversa
PolyanskyAA&ZagrovicB,NAR,18:8434-8443(2013)
Hypotheses
prot
ein
PY
R-a
ffini
ty
mR
NA
PY
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ensi
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Hlevnjak,Polyansky&Zagrovic,NAR,40,2012;Polyansky&Zagrovic,NAR,41,2013;PolyanskyAA,HlevnjakM&ZagrovicB,RNABiology,10,2013;Hajnic,Osorio&Zagrovic,NAR,42,2014;Hajnic,Osorio&Zagrovic,PCCP,17,2015;deRuiter&Zagrovic,NAR,43,2015;Hlevnjak&Zagrovic,NAR,43,2015;Bartonek&Zagrovic,PLOSCB,13,2017
1. our findings support the possibility of aconnecaon between nucleobase/amino-acidbindingandgeneacencoding(suchasinthedirecttempla/ngmechanismofancienttranslaaon)
stereochemicalhypothesis(WoeseCR,1965):
“codingfrombinding”
*
Hypotheses
1. our findings support the possibility of aconnecaon between nucleobase/amino-acidbindingandgeneacencoding(suchasinthedirecttempla/ngmechanismofancienttranslaaon)
prot
ein
PY
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ffini
ty
mR
NA
PY
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2.today’smRNAsandcognateproteinsmaybecomplementarytoeachotherandbind,especiallyifunstructured.ComplementarityisnegaavelyregulatedbymRNAADEcontent.
*
Hlevnjak,Polyansky&Zagrovic,NAR,40,2012;Polyansky&Zagrovic,NAR,41,2013;PolyanskyAA,HlevnjakM&ZagrovicB,RNABiology,10,2013;Hajnic,Osorio&Zagrovic,NAR,42,2014;Hajnic,Osorio&Zagrovic,PCCP,17,2015;deRuiter&Zagrovic,NAR,43,2015;Hlevnjak&Zagrovic,NAR,43,2015;Bartonek&Zagrovic,PLOSCB,13,2017
mRNArecodingvs.cognatematching
codonusagebias
HlevnjakM&ZagrovicB,NAR,43,3012-3021(2015)
prot
ein
pola
r req
uire
men
t
mR
NA
PY
R-d
ensi
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Woesepyridinescale
Func/onalsignificance• PotenaallyrelevantinmanyareasofRNA/proteinbiology:
• translaaonregulaaon• viralcapsidassembly• structureofnon-membrane-boundcellularcompartments• proteininteracaonswithDNA,lncRNAetc.
?enrichmentanalysis
PolyanskyAA,HlevnjakM&ZagrovicB,inprepara#on
PR/PYRmatching
Acasestudy:assemblyoftheMS2bacteriophage
genome%PYRprofile
coatproteinPYRaffinityprofileIDEA:
CPCDS
Daietal.Nature,541,2017
Comparisonagainsta3.6ÅcryoEMstructureofMS2
16high-resoluaonRNAstemloopswithcapsidprotein
R≤-0.6
MS2genome
RNAPYRconten
t
coatproteinPYR
*affi
nityA.coatproteinCDS B.packagingsignal C.replicaseCDS
MS2genome/CPsequence
Profile-basedpredic/onsmatchexperimentalloca/onsofstemloops
A B C
PoetschF,HlevnjakM,PolyanskyAA&ZagrovicB,inpreparaaon
Originofthegene/ccodecodingfrombinding?
Newparadigms?• translaaonregulaaon• viralcapsidassembly• cellularnetworks…
RNA-proteininterac/onsanovelmechanisacperspecave
mRNA-PROTEINCOMPLEMENTARITY
OPENCHALLENGESgeometry;ΔGs;funcaonalsignificance;experimentaltesang
Thanks
Presentmembers• AntonA.Polyansky• LukasBartonek• MarkusFleck• FlorianPötsch• DanielBraun• DanielHoffmann
Formermembers• MateaHajnic• AnitadeRuiter• MarioHlevnjak• JuanOsorioIregui• TheresFriesacher• GeraldPlatzer• AntonijaKuzmanic• DrazenPetrov• DanielaKruschel• ChrisaanMargreiper• MaajaPiskorec• MijoSimunovic• RubenZubac• NatalieRomanov• LilyChen• RaphaelPeer• ThomasMalzac• BiancaMladek• MaudFormanek• AlexanderBeribisky• MathiasKreuter
Collaborators• RobertKonrat,MFPL• ReneeSchroeder,MFPL• KrisanaDjinovic,MFPL• PhilippeH.Huenenberger,ETHZurich• NavrajS.Pannu,LeidenUniversity• CarrieBernecky,ISTA• ChrisOostenbrink,BOKUVienna
Funding