Structure and evolution of IDPs
description
Transcript of Structure and evolution of IDPs
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Structure and evolution Structure and evolution of IDPsof IDPs
Peter Tompa
Institute of EnzymologyHungarian Academy of Sciences
Budapest, Hungary
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Why do we want to Why do we want to characterize/predict IDPs?characterize/predict IDPs?
1) Find new ones (460 in 1) Find new ones (460 in DisProt vs. DisProt vs. tens of thousands)tens of thousands)
2) Describe our 2) Describe our proteinprotein
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Extend the structure-function Extend the structure-function paradigmparadigm
Why do we want to describe the Why do we want to describe the structure of IDPs in detail?structure of IDPs in detail?
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To characterize…
Structure
In the bound state
In the free state
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Structural levels
Structure
Local (secondary)
Global (tertiary)
Sequence (primary)
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1) Primary structure
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Dunker et al. (2001) J. Mol. Graph. Model. 19, 26
Primary structure (sequence) of Primary structure (sequence) of IDPsIDPs
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Low-complexity regions in proteins
Wootton (1994) Comp. Chem. 18, 269
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Low complexity:Low complexity: Drosophila Drosophila mastermindmastermind
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MDAGGLPVFQSASQAAAAAVAQQQQQQQQQQQQQQQQQQQHLNLQLHQQHLQQQQSLGIHLQQQQQLQLQQQQQHNAQAQQQ
QQLQVQQQQQQRQQQQQQQQQHSLYNANLAAAGGIVGGLVPGGNGAGGVALQQVFGGPNGNNNSNNNNNSNNNSININNGNI
SPGDGLPTKRQPILDRLRRRMENYRRRQTDCVPRYEQTFSTVCEQQNHETSALQKRFLESKNKRAAKKTEKKLPETQQQAQT
QMLAGQLQSSVHVQQKILKRPADDVDNGAENYEPPQKLPNNNNNNNNNNNNNNNSSSGVGGGSENLTKFSVEIVQQLEFTTS
AANSQPQQISTNVTVKALTNTSVKSEPGVGGGRGRHQQQQQHQQHQQQQHQQQQHQQHQQHQQQQQHQQQQHQQQQHQQQQQ
QHHHQQQQQQGGGLGGLGNNGRGGGGPGGGGHMATGPGGVGVGMGPNMMSAQQKSALGNLANLVECKREPDHDFPDLGSLAK
DGANGQFPGFPDLLGDDNSENNDTFKDLINNLHDFNPSFLDGFDEKPLLDIKTEDGIKVEPPNAQDLINSLNVKSETGLGHG
FGGFGVGLGLDPQSMKMRPGVGFQNGPNGNANAGNGGPTAGGGGGGNGPGGLMSEHSLAAQTLKQMAEQHQHKSAMGGMGGF
HVPPHGMQQQQPQQQQQAPQQQQQQHGQMMGGPGQGQQQQQQQQPRYNDYGGGFPNDFAMGPNPTQQQQQHLPPQFHQKAPG
GGPGMNVQQNFLDIKQELFYSSPNDFDLKHLQQQQAMQQQQQQQQQQQQQQQHHAQQQQQHPNGPNMGVPMGGAGNFAKQQQ
QQVPTPQQQQQQQLQQQQQQYSPFSNQNANANFLNCPPRGGPQGNQAPGNMPQQQQQQPQQQQQPPRGPQSNPNAVPGGNAA
NATQQQQQQQQQQQQQQQQQQQQQQQATTTTLQMKQTQQLHISQQGGGSHGIQVSAGQHLHLSSDMKSNVSVAAQQGVFFSQ
QQAAQQQQQQQQQPGNAGPNPQQQQQQPHGGNAGANGGGPNGPQQQQPNQNMNNSNVPSDGFSLSQSQSMNFTQQQQQQAAA
AAAAAAAAQQQQAAAAQQQQQQVPPNMRQRQTQAQAAAAAAAAAAAQAQAAANANGGPGGNVPLMQQQQQTPGGVPVGAGSG
NASVGVPVSAGGPNNGAMNQLGGPMGGMPGMQMGGPGGVPINPMQMNPNGGAPNAQMMMGGNGGGPVPAASQAKFLQQQQIM
RAQAMQHQQQVQQHMAGARPPPPEYNATKAQLMQAQMMQQTVGGGGGGGVGVGVGVGGGVGGGGGAGRFPNSAAQAAAMRRM
TQQPIPPSGPMMRPQHAAMYMQQHGGAGGGPRGGMGGPYGGGGVGGAGGPMGGGGGGQQQQQRPPNVQVTPDGMPMGSQQEW
RHMMMTQQQQQMGFGPGGPMRQGPGGFNGGNFMPNGAPNAPGNGPNGGGGGGMMPGPNGPQMQLTPAQMQQQHMRQQQQQQH
MGPGGGGGGGGGNMQMQQLLQQQQNAAAGGGGGMMATQMQMTSIHMSQTQQQQQLTMQQQQFVQSTSTTTTHQQQQQLQLQM
QSQSGGPGGNGPSNNNGANQAGGVGVGVGVGVGVGVVGSSATIASASSISQTINSVVANSNDLCLEFLDNLPDGNFSTQDLI
NSLDNDNFNIQDILQ
Drosophila Drosophila mastermindmastermind
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2) Secondary structure
Structure in the free state (3 examples)
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CREB-KID - CBP-KIX binding and NMR
Radhakrishnan et al. (1998) FEBS Lett. 430, 317
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FlgM: evidence for disorder in vivo
Plaxco and Gross (1997) Nature, 386, 657
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Sorenson (2004) Mol. Cell 14, 127
FlgM - sigma 28 binding and NMR
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p27 p27 – CycA/Cdk2 binding– CycA/Cdk2 binding (NMR, MD) (NMR, MD)
Sivakolundu et al. (2005) JMB 353, 1118
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Wikipedia
SH3-PPII
And a fourth: polyproline II helixAnd a fourth: polyproline II helix
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PPII helix conformation is common in IDPs
Raman optical activity (ROA)
Syme et al. (2002) EJB 269, 148
PPII
Dominates in : -casein -synuclein tau wheat gluten
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2) Secondary structure
Structure in the bound state
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Complexes of IDPs in PDB
p27Kip1 IA3
FnBP
Tcf3
CycA
Cdk2
fibronectin
-catenin
Asp prot.
IUP SP code Length Partner Method CREB P16220 28 CBP KIX NMR
DFF 45 O00273 89 DFF 40 NMR
E-cadherin P09803 57 -catenin X-ray
FCP1 AAC64549.1* 21 TFIIF/RAP74 NMR
FnBPA Q53971 24 Fibronectin NMR
IA3 P01094 29 Proteinase A X-ray
Killer toxin P19972 77 Killer toxin chain X-ray
Bob-1 P10636 13 Pin1 WW NMR
MAP tau P25912 86 DNA X-ray
MAX Q16633 22 Oct-1 POU/DNA X-ray
p27Kip1 P46527 69 CycA-Cdk2 X-ray
p53 P04637 11 MDM 2 X-ray
Phe-tRNA synthetase P27001 79 Phe-tRNA synthetase + tRNA X-ray
PKI P04541 20 PKA X-ray
RB3 Q9H169 91 tubulin X-ray
RNA pol II P04050 17 mRNA capping enzyme X-ray
SNAP 25 P13795-2 77 neuronal fusion complex X-ray
SV 40 virus coat P03087 66 assembled coat X-ray
TAFII230 P51123 67 TBP NMR
TBS virus coat P11795 34 assembled coat X-ray
Tcf3 CAA67686* 41 -catenin X-ray
Tcf4 Q9NQB0 24 -catenin X-ray
Troponin I P19429 17 Troponin C NMR
Vitamin D3R P11473 89 DNA X-ray
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0 20 40 60 80 1000
20
40
60
80
100
Hélixfe
hér
jék
%-a
másodlagos szerkezet %-a
globularIDP
0 20 40 60 80 1000
20
40
60
80
100Extended
feh
érjé
k %
-a
másodlagos szerkezet %-a
0 20 40 60 80 1000
20
40
60
80
100
Turn
feh
érjé
k %
-a
másodlagos szerkezet %-a
0 20 40 60 80 1000
20
40
60
80
100
Coil
feh
érjé
k %
-a
másodlagos szerkezet %-a
Secondary structural elements
31.3 %44.8 %
21.9 %10.9 %
Helix
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Comparison of free and bound states:
what does it tell us ?
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Local secondary structural elements in IDPs:
molecular recognition
1) disorder pattern molecular recognition element
MoRE, MoRF2) consensus sequence:
linear motifLM, ELM, SLiM
3) local predictable structurepreformed structural element
PSE
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1) Disorder pattern: MoRE in tumor suppressor p53
Uversky et al. (2005) J. Mol. Recogn. 18, 343
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2) Consensus sequences: ELMs2) Consensus sequences: ELMs
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ELMs and local disorderELMs and local disorder
Fuxreiter et al (2006) Bioinformatics, 23, 950
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3) Predictability of structure: 3) Predictability of structure: preformed structural elements, preformed structural elements,
PSEsPSEs
p27Kip1 IA3
FnBP
Tcf3
CycA
Cdk2
fibronectin-catenin
Asp prot.
IUP SP code Length Partner Method CREB P16220 28 CBP KIX NMR
DFF 45 O00273 89 DFF 40 NMR
E-cadherin P09803 57 -catenin X-ray
FCP1 AAC64549.1* 21 TFIIF/RAP74 NMR
FnBPA Q53971 24 Fibronectin NMR
IA3 P01094 29 Proteinase A X-ray
Killer toxin P19972 77 Killer toxin chain X-ray
Bob-1 P10636 13 Pin1 WW NMR
MAP tau P25912 86 DNA X-ray
MAX Q16633 22 Oct-1 POU/DNA X-ray
p27Kip1 P46527 69 CycA-Cdk2 X-ray
p53 P04637 11 MDM 2 X-ray
Phe-tRNA synthetase P27001 79 Phe-tRNA synthetase + tRNA X-ray
PKI P04541 20 PKA X-ray
RB3 Q9H169 91 tubulin X-ray
RNA pol II P04050 17 mRNA capping enzyme X-ray
SNAP 25 P13795-2 77 neuronal fusion complex X-ray
SV 40 virus coat P03087 66 assembled coat X-ray
TAFII230 P51123 67 TBP NMR
TBS virus coat P11795 34 assembled coat X-ray
Tcf3 CAA67686* 41 -catenin X-ray
Tcf4 Q9NQB0 24 -catenin X-ray
Troponin I P19429 17 Troponin C NMR
Vitamin D3R P11473 89 DNA X-ray
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Q3 SOV0
20
40
60
80
%
PSE: predictability of secondary structure
IDP
Partner
Fuxreiter et al. (2004) JMB 338, 1015
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MorE, LM, PSE: devices of effective recognition
MoRE
PSE
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Lacy et al (2004) NSMB 11, 358
Sequential mechanism of p27 binding
45
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3) Tertiary structure
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Dedmon et al. (2005) JACS 127, 476
Structural ensemble of a-synuclein
(NMR paramagnetic relaxation enhancement)
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SAXS distance-distribution SAXS distance-distribution function and function and
topology of cellulase Etopology of cellulase E
Von Ossowski et al. (2005) Biophys. J. 88, 2823
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102
103
104
105
106
107
Number of residues
Hy
dro
dy
na
mic
vo
lum
e, Å
3
Native
MGPMG
U (RC)
IUPPM
G
IUPRC
Uversky (2002) Prot. Sci. 11, 739
Global (tertiary) structure of IUPs
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A lesson from denatured states of globular proteins:
Gillespie et al (1997) JMB 268, 170
spatial topology in denatured state resembles native structure (David
Shortle)
p27
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ModelModelss
Protein trinity
Protein quartet
ordered
molten globule
random coil MG RC
ordered PMG
(Dunker) (Uversky)
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The evolution of protein disorder
Evolution
Generation
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Disorder in complete genomes (PONDR)
Dunker et al. (2000) Genome Inf. 11, 161
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Disorder in complete genomes (DISOPRED)
Ward et al. (2004) JMB 337, 635
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IDPs: high frequency in proteomes
Tompa et al. (2006) J. Prot. Res 5, 1996
coli
yeast
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Structural disorder: evolutionary success story
20
40
60
0
LD
R (
40<
) pr
otei
n,
%
Domain of life
B
A
E
Vucetic et al. (2002) Proteins 52, 573
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The evolution of protein disorder
Evolution
Generation
de novo generation
gene duplicationlateral gene transfer, LGT
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The evolution of protein disorder
Evolution
Generation
Mutations
Point mutation
de novo generation
gene duplicationlateral gene transfer, LGT
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Brown et al. (2002) J. Mol. Evol. 55, 104
Rapid evolution by point mutations
0
5
10
15
20
smallersamelargernu
mbe
r of
fam
ilies
evolutionary variability IUP vs glob.
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Non-synonymous vs. synonymous substitutions
Point mutations
Synonymous (Ks)
Non-synonymous (Ka)
Nonsense
Evolution (Ka/Ks):
0.1-0.2: „functional”
1.0: „neutral” 1.0: „adaptive”
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Rapid Rapid evolution of SRY of SRY genegeneSRY: sex determining region on the Y
chromosome (testis determining factor)
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The evolution of protein disorder
Evolution
Generation
Mutations
Point mutation
Repeat expansion
de novo generation
gene duplicationlateral gene transfer, LGT
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RNA polymerase II
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TFs
Initiation
Elongation
Termination
CTDK
RNAP II CTD: coordination of 5’ capping, splicing, 3’ polyadenylation of mRNA
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IGTGAFDVMIDEESLVKYMPEQKITEIEDGQDGGV
TPYSNESGLVNADLDVKDELMFSPLVDSGSNDAMA
GGFTAYGGADYGEATSPFGAYGEAPTSPGFGVSSP
GFSPTSPTYSPTSPAYSPTSPSYSPTSPSYSPTSP
SYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSP
SYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSP
SYSPTSPSYSPTSPAYSPTSPSYSPTSPSYSPTSP
SYSPTSPSYSPTSPNYSPTSPSYSPTSPGYSPGSP
AYSPKQDEQKHNENENSR
Yeast RNAP II CTDYeast RNAP II CTD
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RNAP II CTD evolution
-2.5 -2.0 -1.5 -1.0 -0.5 0.0
10
20
30
40
50
60
time (GYr)
rep
eat
nu
mb
er
-SPSYSPT-
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Repeats in IUPs and other datasets
0
5
10
15
20
25
30
35
40
Swiss-Prot Yeast Human IUP
freq
uenc
y (%
)
protein dataset
proteins
residues
Tompa (2003) BioEssays 25, 847
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Protein
(repeat region)Repeat sequence Repetition Function Type
Calreticulin E/D2-8K/R1-3 6weak, large-capacity calcium
bindingI
Cdk p57 AP 43 linker between domains I
RS protein SC-35 (K)RS 50 mRNA splicing I
mastermind G1-7V/A 7 linker/spacer I
TF GAL11 Q 23assembly of transcription
preinitiation complexI
CPEB Q1-13R/I/L/S 15 regulation of mRNA translation I
Sup35p Q2X2NN/Y 14 Nonsense mutation suppression I
Sry (QQK)0,1Q2-13FHDH1-5 1– 19transactivator domain of sex-
determining factorI
Functional microsatellites (short repeats) in IDPs
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MPRVYIGRLSYNVREKDIQRFFSGYGRLLEVDLKN
GYGFVEFEDSRDADDAVYELNGKELCGERVIVEHA
RGPRRDRDGYSYGSRSGGGGYSSRRTSGRDKYGPP
VRTEYRLIVENLSSRCSWQDLKDFMRQAGEVTYAD
AHKERTNEGVIEFRSYSDMKRALDKLDGTEINGRN
IRLIEDKPRTSHRRSYSGSRSRSRSRRRSRSRSRR
SSRSRSRSISKSRSRSRSRSKGRSRSRSKGRKSRS
KSKSKPKSDRGSHSHSRSRSKDEYEKSRSRSRSRS
PKENGKGDIKSKSRSRSQSRSNSPLPVPPSKARSVSPPPKRATSRSRSRSRSKSRSRSRSSSRD
SFRS6_HUMAN Splicing SFRS6_HUMAN Splicing factorfactor
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MEGHVKRPMNAFMVWSRGERHKLAQQNPSMQNTEISKQLGCRWKSLTEAEKRPFFQEAQRLKILHREKYPNYKYQPHRRAKVSQRSGILQPAVASTKLYNLLQWDRNPHAITYRQDWSRAAHLYSKNQQSFYWQPVDIPTGHLQQQQQQQQQQQFHNHHQQQQQFYDHHQQQQQQQQQQQQFHDHHQQKQQFHDHHQQQQQFHDHHHHHQEQQFHDHHQQQQQFHDHQQQQQQQQQQQFHDHHQQKQQFHDHHHHQQQQQFHDHQQQQQQFHDHQQQQHQFHDHPQQKQQFHDHPQQQQQFHDHHHQQQQKQQFHDHHQQKQQFHDHHQQKQQFHDHHQQQQQFHDHHQQQQQQQQQQQQQFHDQQLTYLLTADITGEHTYQEHLSTALWLAVS
Mouse SRYMouse SRY (testis determining (testis determining factor)factor)
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Protein
(repeat region)Repeat sequence Repetition Function Type
fibronectin-binding protein A (Du-D4)
EDT/SX9,10GGX3,4I/VDF
2 – 5 fibronectin binding I
involucrin (Q-region) QEGQLK/EH/LL/PEQ 24 – 63transglutaminase cross-
linking to form keratinocyte envelope
I
neurofilament-H (KSP domain)
XKSPY1-3K 42 – 55entropic sidearm of
neurofilamentsI
prion protein (octarepeats)
PQ/HGGGWGQ 3 – 14 copper binding III
RNA polymerase II (CTD)
YSPTSPS 11 – 52coordination of
transcription and mRNA processing
II
salivary PRPsPPPGKPQGPPPQGG
NKPQGPP6 – 33
binding of polyphenolic plant compounds
(tannins)I
tau proteinVQ/K/TSKI/CGSL/T/
KD/E/GNI/LK/H/THV/KQPGGG
3 – 5microtubule-binding,
polymerizationI
titin (PEVK)
PEV/APKEVVPEKKA/VPVAPPKKPEV/
APPVKV
5 – 60providing entropic elasticity during
sarcomere stretchI
Functional minisatellites (long repeats) in IDPs
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MSQQHTLPVTLSPALSQELLKTVPPPVNTHQEQMKQPTPLPPPCQKVPVELPVEVPSKQEEKHMTAVKGLPEQECEQQQKEPQEQELQQQHWEQHEEYQKAENPEQQLKQEKTQRDQQLNKQLEEEKKLLDQQLDQELVKRDEQLGMKKEQLLELPEQQEGHLKHLEQQEGQLKHPEQQEGQLELPEQQEGQLELPEQQEGQLELPEQQEGQLELPEQQEGQLELPQQQEGQLELSEQQEGQLELSEQQEGQLELSEQQEGQLKHLEHQEGQLEVPEEQMGQLKYLEQQEGQLKHLDQQEQEGQLEQLEEQEGQLKHLEQQEGQLEHLEHQEGQLGLPEQQVLQLKQLEKQQGQPKHLEEEEGQLKHLVQQEGQLKHLVQQEGQLEQQERQVEHLEQQVGQLKHLEEQEGQLKHLEQQQGQLEVPEQQVGQPKNLEQEEKQLELPEQQEGQVKHLEKQEAQLELPEQQVGQPKHLEQQEKHLEHPEQQDGQLKHLEQQEGQLKDLEQQKGQLEQPVFAPAPGQVQDIQPALPTKGEVLLPVEHQQQKQEVQWPPKHK
INVO_HUMAN InvolucrinINVO_HUMAN Involucrin
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................SDLGLCKKRPKPGGWNTGG
SRYPGQGSPGGNRYPPQGGGGWGQPHGGGWGQPHG
GGWGQPHGGGWGQPHGGGWGQGGGTHSQWNKPSKP
KTNMKHMAGAAAAGAVVGGLGGYMLGSAMSRPIIH
FGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNF
VHDCVNITIKQHTVTTTTKGENFTETDVKMMERVV
EQMCITQYERESQAYYQRGSSMVLFSSPPVILLIS
FLIFLIVG
PRIO_HUMAN major prion protein
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IUPsIUPs often evolve by repeat often evolve by repeat expansionexpansion
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Basic mechanisms of repeat Basic mechanisms of repeat expansionexpansion
Meiotic: replication slippage (micro)
Mitotic: unequal crossing over (mini)
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Wells RD (2001) JBC 271, 2875)
Replication slippageReplication slippage
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(Unequal) crossing (Unequal) crossing overover
Morgan 1916
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Evolution of repetitive regions in IUPs
Tompa (2003) BioEssays 25, 847
Type I
Type II
Type III