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Functional classification of IDPs. Peter Tompa. Institute of Enzymology Hungarian Academy of Sciences Budapest, Hungary. 1. Fun ctional advantages 2. Fun ctional classification (7 basic mechanisms) 3. Func t ion al classification (28 partners-effects)

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slide1

Functional classification of IDPs

Peter Tompa

Institute of Enzymology

Hungarian Academy of Sciences

Budapest, Hungary

slide2

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?

slide5

ii) Specificity without strong binding

(reversibility, inducibility)

slide6

iii) Large binding surfaces in complexes (specificity, multiple partners)

IDP

Globular

Gunasekaran (2004) JMB 341, 1327

slide7

iv) Fast binding

- first observed in DNA renaturation -

hnRNAP A1

no protein

Pontius (1990) PNAS 87, 8403

slide8

”Fly-casting” model

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

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

slide10

v) Binding promiscuity

(one-to-many signaling, moonlighting)

slide13

Disorder correlates with complex size

single

11-100

2-4

5-10

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

slide15

Six basic mechanisms of IDPs

Tompa (2005) FEBS Lett. 579, 3346

slide17

Microtubule-associated protein 2

cytoskeleton

Tubulin dimers

MTs

slide18

MAP projection domain: entropic bristle

Mukhopadhyay (2001) FEBS Lett. 505, 374

slide25

FlgM: inhibitor of sigma28 transcription factor

Plaxco and Gross (1997) Nature, 386, 657

slide28

Casein:

rapid and high-capacity binding of Ca3(PO4)2

Ca3(PO4)2

Ca2+ + PO43-

slide29

MLLILLSVALLALSSAQNLNEDVSQEESPSLIAGNPQGPSP

QGGNKPQGPPPPPGKPQGPPPQGGNKPQGPPPPGKPQGPPP

QGDKSRSPRSPPGKPQGPPPQGGNQPQGPPPPPGKPQGPPP

QGGNKPQGPPPPGKPQGPPPQGDKSQSPRSPPGKPQGPPPQ

GGNQPQGPPPPPGKPQGPPPQGGNKPQGPPPPGKPQGPPPQ

GDKSQSPRSPPGKPQGPPPQGGNQPQGPPPPPGKPQGPPQQ

GGNRPQGPPPPGKPQGPPPQGDKSRSPQSPPGKPQGPPPQG

GNQPQGPPPPPGKPQGPPPQGGNKPQGPPPPGKPQGPPAQG

GSKSQSARAPPGKPQGPPQQEGNNPQGPPPPAGGNPQQPQA

PPAGQPQGPPRPPQGGRPSRPPQ

Baxter (1997) Biochemistry 36, 5566

Salivary PRPs: high-capacity binding of tannins

slide31

p27Kip1

Tcf3

IA3

Cdk2

Asp prot.

FnBP

fibronectin

CycA

b-catenin

Fibronectin binding protein

slide32

High-affinity binding to fibronectin, tethering bacteria to host

Schwarz-Linek (2004) JBC 279, 39017

slide34

Ser133

CREB KID phosphorylation induces binding to CBP KIX domain

PKA

CREB KID

Radhakrishnan (1997) Cell 91, 741

slide37

ELMs and local disorder

Fuxreiter et al (2006) Bioinformatics, 23, 950

slide39

Prediction: very high level of disorder in chaperones

regulatory

signaling

RNA chaperones

protein chaperones

slide41

binding

S transfer

The entropy-transfer model of disordered chaperones

misfolded

folded

IUP

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

slide43

Amyloid: mad-cow disease

Patholopgical prion: structure of PrPC

GPI

*

*

*

(PHGGGWGQ)5

*

*

*

*

P102L

*

*

P107L

*

A127GAAA*AGAVVGGLGG133

slide44

Physiological prion:

Sup35p, eukaryotic translation release factor3

MSNPQDQLSNDLANASISGDQSKQPQQQQPQQQQPY

FNPNQAQAFVPTGGYQQFQPQQQQQYGGYQQNYTQY

QAGGYQQNYNNRGGYQQNYNNRGGYQQNYNNRGGYQ

QQQQQQYQAYNPNQQYGGYQAYNPQQQQQQQTQSQG

MSLADFQKQKAEQQASLNKPAVKKTLKLASSSGIKL

ANATKKVDTAKPAASKEASPAPKDEEASAEPEAKKE

STPVPASSSPAPAAADSTPAPVKKESTPTPSVASKS

APVSASASVVTADALAKEQEDEVDEEVVKDMFGGKD

HVSIIFMGHVDA........

slide48

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

slide49

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

assembler

effector

chaperone

slide50

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

assembler

effector

chaperone

entropic

chain

slide51

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

assembler

effector

chaperone

entropic

chain

prion

slide52

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

scavenger

assembler

effector

chaperone

entropic

chain

prion

slide53

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

scavenger

assembler

effector

chaperone

display

site

entropic

chain

prion

slide54

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

scavenger

assembler

effector

chaperone

display

site

chaperone ?

effector ?

entropic

chain

prion

slide55

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

scavenger

assembler

effector

chaperone

display

site

chaperone ?

effector ?

entropic

chain

effector

prion

slide57

MAP2

The Gene Ontology (GO) scheme

Three ontologies

mol. function

biol. process

cellular component