Functional classification of IDPs

Peter Tompa

Institute of EnzymologyHungarian Academy of Sciences

Budapest, Hungary

1. Functional advantages

2. Functional classification (7 basic mechanisms) 3. Functional classification (28 partners-effects)

4. The relationship of schemes: extension of the GO system?

1) F1) Fununctional advantages of ctional advantages of disorderdisorder

i) Entropic-chain i) Entropic-chain functionsfunctions

ii) Specificity without strong ii) Specificity without strong bindingbinding

(reversibility, inducibility)(reversibility, inducibility)

Gunasekaran (2004) JMB 341, 1327

Globular

IDP

iii) Large binding surfaces in complexes (specificity, multiple

partners)

iv) Fast binding

- first observed in DNA renaturation -

hnRNAP A1

no protein

Pontius (1990) PNAS 87, 8403

”Fly-casting” model

Shoemaker B. A, (2000) PNAS 8868-8873

Speeding molecular recognition by using the folding funnel: the fly-casting mechanism

”Protein fishing” model

clathrin

AP180

v) Binding promiscuityv) Binding promiscuity

(one-to-many signaling, moonlighting)(one-to-many signaling, moonlighting)

ProteinOne (inhibitory)

function Another (activatory)

function Disord

erIUPred (%)

PONDR® (%)

calpastatin inhibition of calpain activation of calpain * 100 80.1

CFTR

(R domain)inhibition of CFTR activation of CFTR * 40.8 53.7

DHPR

(peptide C)inhibition of RyR activation of of RyR * 100 81.1

EBV SMdown-regulation of intron-containing

mRNA

up-regulation of intron-less mRNA

44.1 44.4

MDM2

(180-298)down-regulation of

p21Cip1

activation of estrogen receptor 70.0 70.0

p21Cip1/p27Kip1 inhibition of Cdk activation of Cdk * 48.2 61.0

PIAS1

(392-541)inhibition of

activated STATactivation of p53 41.3 40.7

PPI-2 inhibition of PP1 activation of PP1 * 91.7 77.8

ribosomal L5inhibition of MDM2

ubiquitin ligaseactivation/chaperoning of

ribosome * 22.3 30.8

securininhibition of

separaseactivation/chaperoning of

separase * 52.0 54.2

thymosin- (WH2 domain)

sequestration of G-actin

activation of actin polymerization, ILK kinase * 100 64.3

IUPs with multiple talents: moonlighting

vi) Flexibility in the assembly of vi) Flexibility in the assembly of complexescomplexes

Disorder correlates with complex Disorder correlates with complex sizesize

Hegyi et al. (2007) BMC Struct. Biol. 7, 65

0 20 40 60 80 1000

20

40

60

80

occu

rren

ce

predicted disorder

single

11-100

2-4

5-10

2) F2) Fununctional classification: ctional classification:

7 basic 7 basic mechanismsmechanisms

IUPs

entropic chains recognition

transient binding permanent binding

display sites chaperones effectors assemblers scavengerssites of post-translationalmodification

assist the folding of RNA or protein

modulate theactivity of apartner molecule

assemblecomplexes or target activity

store and/orneutralizesmall ligands

directly functiondue to disorder asspring, bristle, linker

Tompa (2005) FEBS Lett. 579, 3346

Six basic mechanisms of IDPs

IIDDP I:P I: entropi entropic c chainschains

cytoskeleton

MTs

Tubulin dimers

Microtubule-associated protein protein 22

MAP projection domain: entropic bristle

Mukhopadhyay (2001) FEBS Lett. 505, 374

Spacing of MTs in dendrites and axons

V-dependent V-dependent KK++--channelchannel:: e entrntropic opic clockclock

Titin: an entropic spring (like a piece of rubber)

PEVPPVRVPEVPKEVVPEKKVPAAPPKKPEVTPVKVPEAPKEVVPEKK

TTitin PEVK domitin PEVK domaiain: entron: entropic pic springspring

IIDDPs II:Ps II: effectorseffectors

FlgM: inhibitor of sigma28 transcription factor

Plaxco and Gross (1997) Nature, 386, 657

p27: another effector, inhibitor of Cdk2

IIDDPs III:Ps III: scavengersscavengers

Casein: rapid and high-capacity binding of

Ca3(PO4)2

Ca2+ + PO43- Ca3(PO4)2

Salivary PRPs: high-capacity binding of tannins

MLLILLSVALLALSSAQNLNEDVSQEESPSLIAGNPQGPSP

QGGNKPQGPPPPPGKPQGPPPQGGNKPQGPPPPGKPQGPPP

QGDKSRSPRSPPGKPQGPPPQGGNQPQGPPPPPGKPQGPPP

QGGNKPQGPPPPGKPQGPPPQGDKSQSPRSPPGKPQGPPPQ

GGNQPQGPPPPPGKPQGPPPQGGNKPQGPPPPGKPQGPPPQ

GDKSQSPRSPPGKPQGPPPQGGNQPQGPPPPPGKPQGPPQQ

GGNRPQGPPPPGKPQGPPPQGDKSRSPQSPPGKPQGPPPQG

GNQPQGPPPPPGKPQGPPPQGGNKPQGPPPPGKPQGPPAQG

GSKSQSARAPPGKPQGPPQQEGNNPQGPPPPAGGNPQQPQA

PPAGQPQGPPRPPQGGRPSRPPQ Baxter (1997) Biochemistry 36, 5566

IIDDPs IV:Ps IV: assemblersassemblers

45

p27Kip1 IA3

FnBP

Tcf3

CycA

Cdk2

fibronectin

-catenin

Asp prot.

Fibronectin binding protein

High-affinity binding to fibronectin, tethering bacteria

to host

Schwarz-Linek (2004) JBC 279, 39017

IDPs V: display sites

CREB KID phosphorylation induces binding to CBP KIX domain

Radhakrishnan (1997) Cell 91, 741

CREB KID

Ser133

PKA

cAMP-response element binding protein (CREB) activation

The ELM server http://elm.eu.org/

ELMs and local disorderELMs and local disorder

Fuxreiter et al (2006) Bioinformatics, 23, 950

IIDDPs VPs VII:: chaperoneschaperones

30 40 50 60 700

20

40

60

80

pro

tein

s (%

)

minimum length of disorder

Prediction: very high level of disorder in chaperones

regulatorysignalingRNA chaperonesprotein chaperones

Disorder is involved in chaperone function

Tompa and Csermely (2004) Faseb J., 18, 1170-1175

The entropy-transfer model of disordered chaperones

binding S transfer

misfolded folded

IUP

IIDDPs VPs VIIII:: prionsprions

Patholopgical prion: structure of PrPC

(PHGGGWGQ)5

A127GAAA*AGAVVGGLGG133

GPI

***

*

*

**

*

*P107L* P102L

Amyloid: mad-cow disease

Physiological prion:Sup35p, eukaryotic translation release

factor3

MSNPQDQLSNDLANASISGDQSKQPQQQQPQQQQPY

FNPNQAQAFVPTGGYQQFQPQQQQQYGGYQQNYTQY

QAGGYQQNYNNRGGYQQNYNNRGGYQQNYNNRGGYQ

QQQQQQYQAYNPNQQYGGYQAYNPQQQQQQQTQSQG

MSLADFQKQKAEQQASLNKPAVKKTLKLASSSGIKL

ANATKKVDTAKPAASKEASPAPKDEEASAEPEAKKE

STPVPASSSPAPAAADSTPAPVKKESTPTPSVASKS

APVSASASVVTADALAKEQEDEVDEEVVKDMFGGKD

HVSIIFMGHVDA........

Prion form of Sup35: translation read-through

Prion form of Sup35: translation read-through

3) F3) Fununctional classification: ctional classification:

28 partners-28 partners-effectseffects

Functional classification of IDPs, Dunker 2002

protein-protein binding protein-DNA binding protein-rRNA binding protein-tRNA binding protein-mRNA binding protein-genomic RNA binding protein-lipid interaction

flexible linkers/spacers entropic spring entropic bristle entropic clock structural mortar protein detergent self-transport through channel

polymerization

substrate/ligand binding cofactor/heme binding metal binding

acetylation fatty acylation (myristoyl/palmitoyl)glycosylation methylation phosphorylation ADP-ribosylation

DNA unwinding DNA bending

reg. of proteolysis in vivo

autoregulatory not essential/unknown

protein-protein binding protein-DNA binding protein-rRNA binding protein-tRNA binding protein-mRNA binding protein-genomic RNA binding protein-lipid interaction

flexible linkers/spacers entropic spring entropic bristle entropic clock structural mortar protein detergent self-transport through channel

polymerization

substrate/ligand binding cofactor/heme binding metal binding

acetylation fatty acylation (myristoyl/palmitoyl)glycosylation methylation phosphorylation ADP-ribosylation

DNA unwinding DNA bending

reg. of proteolysis in vivo

autoregulatory not essential/unknown

assemblereffector

chaperone

Functional classification of IDPs, Dunker 2002

protein-protein binding protein-DNA binding protein-rRNA binding protein-tRNA binding protein-mRNA binding protein-genomic RNA binding protein-lipid interaction

flexible linkers/spacers entropic spring entropic bristle entropic clock structural mortar protein detergent self-transport through channel

polymerization

substrate/ligand binding cofactor/heme binding metal binding

acetylation fatty acylation (myristoyl/palmitoyl)glycosylation methylation phosphorylation ADP-ribosylation

DNA unwinding DNA bending

reg. of proteolysis in vivo

autoregulatory not essential/unknown

assemblereffector

chaperone

entropic chain

Functional classification of IDPs, Dunker 2002

protein-protein binding protein-DNA binding protein-rRNA binding protein-tRNA binding protein-mRNA binding protein-genomic RNA binding protein-lipid interaction

flexible linkers/spacers entropic spring entropic bristle entropic clock structural mortar protein detergent self-transport through channel

polymerization

substrate/ligand binding cofactor/heme binding metal binding

acetylation fatty acylation (myristoyl/palmitoyl)glycosylation methylation phosphorylation ADP-ribosylation

DNA unwinding DNA bending

reg. of proteolysis in vivo

autoregulatory not essential/unknown

assemblereffector

chaperone

entropic chain

prion

Functional classification of IDPs, Dunker 2002

protein-protein binding protein-DNA binding protein-rRNA binding protein-tRNA binding protein-mRNA binding protein-genomic RNA binding protein-lipid interaction

flexible linkers/spacers entropic spring entropic bristle entropic clock structural mortar protein detergent self-transport through channel

polymerization

substrate/ligand binding cofactor/heme binding metal binding

acetylation fatty acylation (myristoyl/palmitoyl)glycosylation methylation phosphorylation ADP-ribosylation

DNA unwinding DNA bending

reg. of proteolysis in vivo

autoregulatory not essential/unknown

assemblereffector

chaperone

entropic chain

prion

scavenger

Functional classification of IDPs, Dunker 2002

protein-protein binding protein-DNA binding protein-rRNA binding protein-tRNA binding protein-mRNA binding protein-genomic RNA binding protein-lipid interaction

flexible linkers/spacers entropic spring entropic bristle entropic clock structural mortar protein detergent self-transport through channel

polymerization

substrate/ligand binding cofactor/heme binding metal binding

acetylation fatty acylation (myristoyl/palmitoyl)glycosylation methylation phosphorylation ADP-ribosylation

DNA unwinding DNA bending

reg. of proteolysis in vivo

autoregulatory not essential/unknown

assemblereffector

chaperone

entropic chain

prion

scavenger

displaysite

Functional classification of IDPs, Dunker 2002

protein-protein binding protein-DNA binding protein-rRNA binding protein-tRNA binding protein-mRNA binding protein-genomic RNA binding protein-lipid interaction

flexible linkers/spacers entropic spring entropic bristle entropic clock structural mortar protein detergent self-transport through channel

polymerization

substrate/ligand binding cofactor/heme binding metal binding

acetylation fatty acylation (myristoyl/palmitoyl)glycosylation methylation phosphorylation ADP-ribosylation

DNA unwinding DNA bending

reg. of proteolysis in vivo

autoregulatory not essential/unknown

assemblereffector

chaperone

entropic chain

prion

scavenger

displaysite

chaperone ?effector ?

Functional classification of IDPs, Dunker 2002

protein-protein binding protein-DNA binding protein-rRNA binding protein-tRNA binding protein-mRNA binding protein-genomic RNA binding protein-lipid interaction

flexible linkers/spacers entropic spring entropic bristle entropic clock structural mortar protein detergent self-transport through channel

polymerization

substrate/ligand binding cofactor/heme binding metal binding

acetylation fatty acylation (myristoyl/palmitoyl)glycosylation methylation phosphorylation ADP-ribosylation

DNA unwinding DNA bending

reg. of proteolysis in vivo

autoregulatory not essential/unknown

assemblereffector

chaperone

entropic chain

prion

scavenger

displaysite

effector

chaperone ?effector ?

Functional classification of IDPs, Dunker 2002

4) Extension of the GO 4) Extension of the GO scheme ?scheme ?

The Gene Ontology (GO) scheme

Three ontologies

mol. function

biol. process

cellular component

MAP2