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Structure and evolution of IDPs. Peter Tompa. Institute of Enzymology Hungarian Academy of Sciences Budapest, Hungary. Why do we want to characterize/predict IDPs?. 1) Find new ones (460 in DisProt vs. tens of thousands). 2) Describe our protein.

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Structure and evolution of IDPs

Peter Tompa

Institute of Enzymology

Hungarian Academy of Sciences

Budapest, Hungary


Why do we want to characterize/predict IDPs?

1) Find new ones (460 in DisProt vs. tens of thousands)

2) Describe our protein


Why do we want to describe the structure of IDPs in detail?

Extend the structure-function paradigm


To characterize…

In the free state

Structure

In the bound state


Structural levels

Sequence (primary)

Local (secondary)

Structure

Global (tertiary)



Primary structure (sequence) of IDPs

Dunker et al. (2001) J. Mol. Graph. Model. 19, 26


Low-complexity regions in proteins

Wootton (1994) Comp. Chem. 18, 269


Low complexity:Drosophila mastermind


Drosophila mastermind

MDAGGLPVFQSASQAAAAAVAQQQQQQQQQQQQQQQQQQQHLNLQLHQQHLQQQQSLGIHLQQQQQLQLQQQQQHNAQAQQQ

QQLQVQQQQQQRQQQQQQQQQHSLYNANLAAAGGIVGGLVPGGNGAGGVALQQVFGGPNGNNNSNNNNNSNNNSININNGNI

SPGDGLPTKRQPILDRLRRRMENYRRRQTDCVPRYEQTFSTVCEQQNHETSALQKRFLESKNKRAAKKTEKKLPETQQQAQT

QMLAGQLQSSVHVQQKILKRPADDVDNGAENYEPPQKLPNNNNNNNNNNNNNNNSSSGVGGGSENLTKFSVEIVQQLEFTTS

AANSQPQQISTNVTVKALTNTSVKSEPGVGGGRGRHQQQQQHQQHQQQQHQQQQHQQHQQHQQQQQHQQQQHQQQQHQQQQQ

QHHHQQQQQQGGGLGGLGNNGRGGGGPGGGGHMATGPGGVGVGMGPNMMSAQQKSALGNLANLVECKREPDHDFPDLGSLAK

DGANGQFPGFPDLLGDDNSENNDTFKDLINNLHDFNPSFLDGFDEKPLLDIKTEDGIKVEPPNAQDLINSLNVKSETGLGHG

FGGFGVGLGLDPQSMKMRPGVGFQNGPNGNANAGNGGPTAGGGGGGNGPGGLMSEHSLAAQTLKQMAEQHQHKSAMGGMGGF

HVPPHGMQQQQPQQQQQAPQQQQQQHGQMMGGPGQGQQQQQQQQPRYNDYGGGFPNDFAMGPNPTQQQQQHLPPQFHQKAPG

GGPGMNVQQNFLDIKQELFYSSPNDFDLKHLQQQQAMQQQQQQQQQQQQQQQHHAQQQQQHPNGPNMGVPMGGAGNFAKQQQ

QQVPTPQQQQQQQLQQQQQQYSPFSNQNANANFLNCPPRGGPQGNQAPGNMPQQQQQQPQQQQQPPRGPQSNPNAVPGGNAA

NATQQQQQQQQQQQQQQQQQQQQQQQATTTTLQMKQTQQLHISQQGGGSHGIQVSAGQHLHLSSDMKSNVSVAAQQGVFFSQ

QQAAQQQQQQQQQPGNAGPNPQQQQQQPHGGNAGANGGGPNGPQQQQPNQNMNNSNVPSDGFSLSQSQSMNFTQQQQQQAAA

AAAAAAAAQQQQAAAAQQQQQQVPPNMRQRQTQAQAAAAAAAAAAAQAQAAANANGGPGGNVPLMQQQQQTPGGVPVGAGSG

NASVGVPVSAGGPNNGAMNQLGGPMGGMPGMQMGGPGGVPINPMQMNPNGGAPNAQMMMGGNGGGPVPAASQAKFLQQQQIM

RAQAMQHQQQVQQHMAGARPPPPEYNATKAQLMQAQMMQQTVGGGGGGGVGVGVGVGGGVGGGGGAGRFPNSAAQAAAMRRM

TQQPIPPSGPMMRPQHAAMYMQQHGGAGGGPRGGMGGPYGGGGVGGAGGPMGGGGGGQQQQQRPPNVQVTPDGMPMGSQQEW

RHMMMTQQQQQMGFGPGGPMRQGPGGFNGGNFMPNGAPNAPGNGPNGGGGGGMMPGPNGPQMQLTPAQMQQQHMRQQQQQQH

MGPGGGGGGGGGNMQMQQLLQQQQNAAAGGGGGMMATQMQMTSIHMSQTQQQQQLTMQQQQFVQSTSTTTTHQQQQQLQLQM

QSQSGGPGGNGPSNNNGANQAGGVGVGVGVGVGVGVVGSSATIASASSISQTINSVVANSNDLCLEFLDNLPDGNFSTQDLI

NSLDNDNFNIQDILQ


2) Secondary structure

Structure in the free state (3 examples)


CREB-KID - CBP-KIX binding and NMR

Radhakrishnan et al. (1998) FEBS Lett. 430, 317


FlgM: evidence for disorder in vivo

Plaxco and Gross (1997) Nature, 386, 657


FlgM - sigma 28 binding and NMR

Sorenson (2004) Mol. Cell 14, 127


p27 – CycA/Cdk2 binding (NMR, MD)

Sivakolundu et al. (2005) JMB 353, 1118



PPII

PPII helix conformation is common in IDPs

Dominates in :

a-casein

a-synuclein

tau

wheat gluten

Raman optical activity (ROA)

Syme et al. (2002) EJB 269, 148


2) Secondary structure

Structure in the bound state


p27Kip1

Tcf3

IA3

Cdk2

Asp prot.

FnBP

fibronectin

CycA

b-catenin

Complexes of IDPs in PDB


31.3 %

21.9 %

44.8 %

10.9 %

Secondary structural elements

Helix

globular

IDP


Comparison of free and bound states:

what does it tell us ?


Local secondary structural elements in IDPs:

molecular recognition

1) disorder pattern

molecular recognition element

MoRE, MoRF

2) consensus sequence:

linear motif

LM, ELM, SLiM

3) local predictable structure

preformed structural element

PSE


1) Disorder pattern: MoRE in tumor suppressor p53

Uversky et al. (2005) J. Mol. Recogn. 18, 343



ELMs and local disorder

Fuxreiter et al (2006) Bioinformatics, 23, 950


3) Predictability of structure: preformed structural elements, PSEs

p27Kip1

Tcf3

IA3

Cdk2

Asp prot.

FnBP

fibronectin

CycA

b-catenin


PSE: p elements, PSEsredictability of secondary structure

IDP

Partner

Fuxreiter et al. (2004) JMB 338, 1015


MoRE elements, PSEs

PSE

MorE, LM, PSE: devices of effective recognition


Sequential mechanism of p27 binding elements, PSEs

45

Lacy et al (2004) NSMB 11, 358


3) Tertiary structure elements, PSEs


Structural ensemble of a-synuclein elements, PSEs

(NMR paramagnetic relaxation enhancement)

Dedmon et al. (2005) JACS 127, 476


SAXS distance-distribution function and elements, PSEs

topology of cellulase E

Von Ossowski et al. (2005) Biophys. J. 88, 2823


Global (tertiary) structure of IUPs elements, PSEs

IUPRC

U (RC)

IUPPMG

PMG

MG

Native

Uversky (2002) Prot. Sci. 11, 739


p27 elements, PSEs

A lesson from denatured states of globular proteins:

spatial topology in denatured state resembles native structure (David Shortle)

Gillespie et al (1997) JMB 268, 170


Model elements, PSEss

Protein trinity

Protein quartet

ordered

ordered

PMG

molten globule

random coil

MG

RC

(Dunker)

(Uversky)


The elements, PSEsevolution of protein disorder

Generation

Evolution


Disorder in complete genomes (PONDR) elements, PSEs

Dunker et al. (2000) Genome Inf. 11, 161


Disorder in complete genomes (DISOPRED) elements, PSEs

Ward et al. (2004) JMB 337, 635


I elements, PSEsDPs: high frequency in proteomes

yeast

coli

Tompa et al. (2006) J. Prot. Res5, 1996


Structural disorder: evolutionary success story elements, PSEs

LDR (40<) protein, %

60

E

40

A

20

B

0

Domain of life

Vucetic et al. (2002) Proteins 52, 573


The elements, PSEsevolution of protein disorder

de novogeneration

Generation

gene duplication

lateral gene transfer, LGT

Evolution


The elements, PSEsevolution of protein disorder

de novogeneration

Generation

gene duplication

lateral gene transfer, LGT

Evolution

Pointmutation

Mutations


Rapid elements, PSEs evolution by point mutations

Brown et al. (2002) J. Mol. Evol. 55, 104


Non-synonymous vs. synonymous substitutions elements, PSEs

Synonymous (Ks)

Point mutations

Non-synonymous (Ka)

Nonsense

0.1-0.2: „functional”

Evolution (Ka/Ks):

1.0: „neutral”

1.0: „adaptive”


Rapid elements, PSEsevolution of SRY gene

SRY: sex determining region on the Y chromosome

(testis determining factor)


The elements, PSEsevolution of protein disorder

de novogeneration

Generation

gene duplication

lateral gene transfer, LGT

Evolution

Pointmutation

Mutations

Repeat expansion


RNA elements, PSEs polymerase II


RNAP II CTD: coordination of 5’ capping, splicing, 3’ polyadenylation of mRNA

TFs

Initiation

Elongation

Termination

CTDK


Yeast RNAP II CTD polyadenylation

IGTGAFDVMIDEESLVKYMPEQKITEIEDGQDGGV

TPYSNESGLVNADLDVKDELMFSPLVDSGSNDAMA

GGFTAYGGADYGEATSPFGAYGEAPTSPGFGVSSP

GFSPTSPTYSPTSPAYSPTSPSYSPTSPSYSPTSP

SYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSP

SYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSP

SYSPTSPSYSPTSPAYSPTSPSYSPTSPSYSPTSP

SYSPTSPSYSPTSPNYSPTSPSYSPTSPGYSPGSP

AYSPKQDEQKHNENENSR


RNAP II CTD evolution polyadenylation

repeat number

-SPSYSPT-

time (GYr)


Repeats in IUPs and other datasets polyadenylation

proteins

residues

Tompa (2003) BioEssays 25, 847


Functional microsatellites polyadenylation (short repeats) in IDPs


SFRS6_HUMAN Splicing factor polyadenylation

MPRVYIGRLSYNVREKDIQRFFSGYGRLLEVDLKN

GYGFVEFEDSRDADDAVYELNGKELCGERVIVEHA

RGPRRDRDGYSYGSRSGGGGYSSRRTSGRDKYGPP

VRTEYRLIVENLSSRCSWQDLKDFMRQAGEVTYAD

AHKERTNEGVIEFRSYSDMKRALDKLDGTEINGRN

IRLIEDKPRTSHRRSYSGSRSRSRSRRRSRSRSRR

SSRSRSRSISKSRSRSRSRSKGRSRSRSKGRKSRS

KSKSKPKSDRGSHSHSRSRSKDEYEKSRSRSRSRS

PKENGKGDIKSKSRSRSQSRSNSPLPVPPSKARSV

SPPPKRATSRSRSRSRSKSRSRSRSSSRD


Mouse SRY polyadenylation (testis determining factor)

MEGHVKRPMNAFMVWSRGERHKLAQQNPSMQNTEISKQLGCRWKSLTEAEKRPFFQEAQRLKILHREKYPNYKYQPHRRAKVSQRSGILQPAVASTKLYNLLQWDRNPHAITYRQDWSRAAHLYSKNQQSFYWQPVDIPTGHLQQQQQQQQQQQFHNHHQQQQQFYDHHQQQQQQQQQQQQFHDHHQQKQQFHDHHQQQQQFHDHHHHHQEQQFHDHHQQQQQFHDHQQQQQQQQQQQFHDHHQQKQQFHDHHHHQQQQQFHDHQQQQQQFHDHQQQQHQFHDHPQQKQQFHDHPQQQQQFHDHHHQQQQKQQFHDHHQQKQQFHDHHQQKQQFHDHHQQQQQFHDHHQQQQQQQQQQQQQFHDQQLTYLLTADITGEHTYQEHLSTALWLAVS


Functional minisatellites polyadenylation(long repeats) in IDPs


INVO_HUMAN Involucrin polyadenylation

MSQQHTLPVTLSPALSQELLKTVPPPVNTHQEQMK

QPTPLPPPCQKVPVELPVEVPSKQEEKHMTAVKGL

PEQECEQQQKEPQEQELQQQHWEQHEEYQKAENPE

QQLKQEKTQRDQQLNKQLEEEKKLLDQQLDQELVK

RDEQLGMKKEQLLELPEQQEGHLKHLEQQEGQLKH

PEQQEGQLELPEQQEGQLELPEQQEGQLELPEQQE

GQLELPEQQEGQLELPQQQEGQLELSEQQEGQLEL

SEQQEGQLELSEQQEGQLKHLEHQEGQLEVPEEQM

GQLKYLEQQEGQLKHLDQQEQEGQLEQLEEQEGQL

KHLEQQEGQLEHLEHQEGQLGLPEQQVLQLKQLEK

QQGQPKHLEEEEGQLKHLVQQEGQLKHLVQQEGQL

EQQERQVEHLEQQVGQLKHLEEQEGQLKHLEQQQG

QLEVPEQQVGQPKNLEQEEKQLELPEQQEGQVKHL

EKQEAQLELPEQQVGQPKHLEQQEKHLEHPEQQDG

QLKHLEQQEGQLKDLEQQKGQLEQPVFAPAPGQVQ

DIQPALPTKGEVLLPVEHQQQKQEVQWPPKHK


PRIO_HUMAN polyadenylationmajor prion protein

................SDLGLCKKRPKPGGWNTGG

SRYPGQGSPGGNRYPPQGGGGWGQPHGGGWGQPHG

GGWGQPHGGGWGQPHGGGWGQGGGTHSQWNKPSKP

KTNMKHMAGAAAAGAVVGGLGGYMLGSAMSRPIIH

FGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNF

VHDCVNITIKQHTVTTTTKGENFTETDVKMMERVV

EQMCITQYERESQAYYQRGSSMVLFSSPPVILLIS

FLIFLIVG


IUPs polyadenylation often evolve by repeat expansion


Basic mechanisms of repeat expansion polyadenylation

Meiotic: replication slippage (micro)

Mitotic: unequal crossing over (mini)


Replication slippage polyadenylation

Wells RD (2001) JBC 271, 2875)


(Unequal) crossing over polyadenylation

Morgan 1916


Evolution of repetitive regions in IUPs polyadenylation

Tompa (2003) BioEssays 25, 847


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