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

R-d

ensi

ty

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

R-a

ffini

ty

mR

NA

PY

R-d

ensi

ty

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

ty

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