Download - Functional classification of IDPs
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