Download Functional classification of IDPs

Functional classification of IDPs
Peter Tompa
Institute of Enzymology
Hungarian 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) Functional advantages of disorder
i) Entropic-chain functions
ii) Specificity without strong binding
(reversibility, inducibility)
iii) Large binding surfaces in complexes
(specificity, multiple partners)
IDP
Globular
Gunasekaran (2004) JMB 341, 1327
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 promiscuity
(one-to-many signaling, moonlighting)
IUPs with multiple talents: moonlighting
Protein
One (inhibitory)
function
Another (activatory)
function
Disord
er
IUPre
d (%)
PONDR
® (%)
calpastatin
inhibition of calpain
activation of calpain
100
80.1
inhibition of CFTR
activation of CFTR
*
*
40.8
53.7
inhibition of RyR
activation of of RyR
*
100
81.1
EBV SM
down-regulation of
up-regulation of intron-less
intron-containing
mRNA
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 STAT
activation of p53
41.3
40.7
PPI-2
inhibition of PP1
activation of PP1
91.7
77.8
inhibition of MDM2
ubiquitin ligase
inhibition of
separase
sequestration of Gactin
activation/chaperoning of
ribosome
activation/chaperoning of
separase
activation of actin
polymerization, ILK kinase
22.3
30.8
52.0
54.2
100
64.3
CFTR
(R domain)
DHPR
(peptide C)
ribosomal L5
securin
thymosin-
(WH2 domain)
*
*
*
*
*
vi) Flexibility in the assembly of complexes
Disorder correlates with complex size
single
80
11-100
occurrence
60
2-4
40
5-10
20
0
0
20
40
60
80
100
predicted disorder
Hegyi et al. (2007) BMC Struct. Biol. 7, 65
2) Functional classification:
7 basic mechanisms
Six basic mechanisms of IDPs
IUPs
recognition
entropic chains
directly function
due to disorder as
spring, bristle, linker
transient binding
permanent binding
display sites
chaperones
effectors
assemblers
scavengers
sites of posttranslational
modification
assist the folding
of RNA or protein
modulate the
activity of a
partner molecule
assemble
complexes or
target activity
store and/or
neutralize
small ligands
Tompa (2005) FEBS Lett. 579, 3346
IDP I: entropic chains
Microtubule-associated protein 2
cytoskeleton
Tubulin
dimers
MTs
MAP projection domain: entropic bristle
Mukhopadhyay (2001) FEBS Lett. 505, 374
Spacing of MTs in dendrites and axons
V-dependent K+-channel: entropic clock
Titin: an entropic spring (like a piece of rubber)
PEVPPVRVPEVPKEVV
PEKKVPAAPPKKPEVT
PVKVPEAPKEVVPEKK
Titin PEVK domain: entropic spring
IDPs II: effectors
FlgM: inhibitor of sigma28 transcription factor
Plaxco and Gross (1997) Nature, 386, 657
p27: another effector, inhibitor of Cdk2
IDPs III: scavengers
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
IDPs IV: assemblers
45
Fibronectin binding protein
p27Kip1
Tcf3
IA3
Cdk2
FnBP
CycA
Asp prot.
fibronectin
-catenin
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
Ser133
CREB KID
Radhakrishnan (1997) Cell 91, 741
cAMP-response element binding protein (CREB)
activation
The ELM server http://elm.eu.org/
ELMs and local disorder
Fuxreiter et al (2006) Bioinformatics, 23, 950
IDPs VI: chaperones
Prediction: very high level of disorder in
chaperones
regulatory
signaling
RNA chaperones
protein chaperones
80
proteins (%)
60
40
20
0
30
40
50
60
minimum length of disorder
70
Disorder is involved in chaperone function
The entropy-transfer model of disordered
chaperones
misfolded
folded
IUP
binding
S transfer
Tompa and Csermely (2004) Faseb J., 18, 1170-1175
IDPs VII: prions
Patholopgical prion: structure of PrPC
GPI
*
**
(PHGGGWGQ)5
*
*
*
*
* P102L
* P107L
*
A127GAAA*AGAVVGGLGG133
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) Functional classification:
28 partners-effects
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
Functional classification of IDPs, Dunker 2002
protein-protein binding
protein-DNA binding
protein-rRNA
binding
assembler
protein-tRNA
binding
effector
protein-mRNA binding
chaperone
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
Functional classification of IDPs, Dunker 2002
protein-protein binding
protein-DNA binding
protein-rRNA
binding
assembler
protein-tRNA
binding
effector
protein-mRNA binding
chaperone
protein-genomic
RNA
binding
protein-lipid interaction
flexible linkers/spacers
entropic spring
entropic bristle
entropic
entropic
clock
structural mortar
chain
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
Functional classification of IDPs, Dunker 2002
protein-protein binding
protein-DNA binding
protein-rRNA
binding
assembler
protein-tRNA
binding
effector
protein-mRNA binding
chaperone
protein-genomic
RNA
binding
protein-lipid interaction
flexible linkers/spacers
entropic spring
entropic bristle
entropic
entropic
clock
structural mortar
chain
protein detergent
self-transport through
channel
prion
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
Functional classification of IDPs, Dunker 2002
protein-protein binding
protein-DNA binding
protein-rRNA
binding
assembler
protein-tRNA
binding
effector
protein-mRNA binding
chaperone
protein-genomic
RNA
binding
protein-lipid interaction
flexible linkers/spacers
entropic spring
entropic bristle
entropic
entropic
clock
structural mortar
chain
protein detergent
self-transport through
channel
prion
polymerization
substrate/ligand binding
scavenger
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
Functional classification of IDPs, Dunker 2002
protein-protein binding
protein-DNA binding
protein-rRNA
binding
assembler
protein-tRNA
binding
effector
protein-mRNA binding
chaperone
protein-genomic
RNA
binding
protein-lipid interaction
flexible linkers/spacers
entropic spring
entropic bristle
entropic
entropic
clock
structural mortar
chain
protein detergent
self-transport through
channel
prion
polymerization
substrate/ligand binding
scavenger
cofactor/heme
binding
metal binding
acetylation
fatty acylation
(myristoyl/palmitoyl)
display
glycosylation
site
methylation
phosphorylation
ADP-ribosylation
DNA unwinding
DNA bending
reg. of proteolysis in vivo
autoregulatory
not essential/unknown
Functional classification of IDPs, Dunker 2002
protein-protein binding
protein-DNA binding
protein-rRNA
binding
assembler
protein-tRNA
binding
effector
protein-mRNA binding
chaperone
protein-genomic
RNA
binding
protein-lipid interaction
flexible linkers/spacers
entropic spring
entropic bristle
entropic
entropic
clock
structural mortar
chain
protein detergent
self-transport through
channel
prion
polymerization
substrate/ligand binding
scavenger
cofactor/heme
binding
metal binding
acetylation
fatty acylation
(myristoyl/palmitoyl)
display
glycosylation
site
methylation
phosphorylation
ADP-ribosylation
chaperone ?
DNA unwinding
DNA bending
effector ?
reg. of proteolysis in vivo
autoregulatory
not essential/unknown
Functional classification of IDPs, Dunker 2002
protein-protein binding
protein-DNA binding
protein-rRNA
binding
assembler
protein-tRNA
binding
effector
protein-mRNA binding
chaperone
protein-genomic
RNA
binding
protein-lipid interaction
flexible linkers/spacers
entropic spring
entropic bristle
entropic
entropic
clock
structural mortar
chain
protein detergent
self-transport through
channel
prion
polymerization
substrate/ligand binding
scavenger
cofactor/heme
binding
metal binding
acetylation
fatty acylation
(myristoyl/palmitoyl)
display
glycosylation
site
methylation
phosphorylation
ADP-ribosylation
chaperone ?
DNA unwinding
DNA bending
effector ?
effectorin vivo
reg. of proteolysis
autoregulatory
not essential/unknown
4) Extension of the GO scheme ?
The Gene Ontology (GO) scheme
Three ontologies
mol. function
biol. process
cellular component
MAP2