structural disorder, prions, amyloids and polyglutamine diseases institute of enzymology hungarian...
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Structural disorder,Structural disorder,
prions, prions, amamyyloidloids and s and polpolyyglutaminglutaminee diseasesdiseases
Institute of EnzymologyHungarian Academy of Sciences
Budapest, Hungary
Peter Tompa
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AmAmyyloid loid diseasesdiseases
Disease Protein/peptide Aggregate
Alzheimer’s disease
Primary systemic amyloidosis
Senile systemic amyloidosis
Diabetes type II
Hemodialysis-associated amyloidosis
Familial systemic amyloidosis
Huntingon’s disease
Parkinson’s disease
CJD, other prion diseases
Taupathies, Pick disease, FTDP-17
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Amyloid diseases: “traditional” classification
systemic vs. tissue-specific
juvenile vs. adult or old
inherited vs. spontaneous
primary vs. secondary
protein vs. peptide
mass in kgs vs. almost negligible
(globular vs. IUP)
so what is common ???
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Amyloid fibrils
• 10 nm
• straight
• stable
• tinctorial properties (Congo red)
• cross-b
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Symptoms fall into two broad classes
Systemic cases
- organ failure (heart, liver, kidney)
Tissue-specific cases
- cognitive impairment (dementia, often with psychiatric symptoms)
- loss of coordination of movement
- neurodegeneration
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Amyloid diseases
Disease Protein/peptide Aggregate
Alzheimer’s disease A Senile plaq
Primary systemic amyloidosis Ig light chain
Senile systemic amyloidosis Transthyretin
Diabetes type II Amylin
Hemodialysis-associated amyloidosis 2-microglobulin
Familial systemic amyloidosis Lysozyme mutant
Huntingon’s disease Huntingtin Huntingtin inclusion
Parkinson’s disease -synuclein Lewy body
CJD, other prion diseases PrPSc Prion aggregate
Taupathies, Pick disease, FTDP-17 Tau protein PHF, Pick-body
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1) Protein (AL, ATTR, ALys)
2) Cause (spontaneous, mutation, induced)
3) Mechanism (loss or gain of function)
Amyloid diseases: modern classification
protein misfolding diseases
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AD plaque Neurofibrillary tangle (PHF)
Alzheimer’s disease
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Amyloid precursor protein (APP)
(TACE, ADAM10)
(PSEN)
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„Lag-phase” and „seeding” (1D crystal growth)
Chen et al. (2001) JMB 311, 173
Long
incubation time
Exponential growth
„Seeding”
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Familial systemic amyloidosis:
LLysysozozyymmee mut mutantsants
I56T
D67H
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Reduced stability of amyloidogenic mutants
Wild type
Ile56Thr
Asp67His
Booth et al. (1997) Nature 385, 787
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normal
kidney
liver
123I-SAP scintigraphy
Pepys
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Huntington’s disease (Huntingtin)
MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQPLLPQPQPPPPPPPPPPGPAVAEEPLHRPKKELSATKKDRVNHCLTICENIVAQSVRNSPEFQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKALMDSNLPRLQLELYKEIKKNG…
ATGGCGACCCTGGAAAAGCTGATGAAGGCCTTCGAGTCCCTCAAGTCCTTCCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAACAGCCGCCACCGCCGCCGCCGCCGCCGCCGCCTCCTCAGCTTCCTCAGCCGCCGCCGCAGGCACAGCCGCTGCTGCCTCAGCCGCAGCCGCCCCCGCCGCCGCCCCCGCCGCCACCCGGCCCGGCTGTGGCTGAGGAGCCGCTGCACCGACCAAAGAAAGAACTTTCAGCTACCAAGAAAGACC…
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PolyQ expansion: polymorphisms
Wells (1996) JBC 271, 2875
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Huntingtin inclusions in neuronal nuclei
Perutz (1999) TiBS 24, 58
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Cause of disease?
Loss of function
Gain of function
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Anticipation in polyQ-disease inheritance
- dynamic mutation, mutable mutation -
Tsuji (1997) Int. Med. 36, 3
Ag
e o
f on
set,
DR
PLA
CAG repeat units
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Prion diseases (TSE)
ANIMALANIMAL
SCRAPIESCRAPIE sheepsheep
BSEBSE bovinebovine
TMETME minkmink
CWDCWD deerdeer
FSEFSE catcat
HUMANHUMAN
kurukuru
CJD (Creutzfeldt-Jakob)CJD (Creutzfeldt-Jakob)
GSS (Gerstmann,Straussler, GSS (Gerstmann,Straussler,
Sheinker)Sheinker)
FFIFFI
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• rapid cognitive impairment (dementia)• movement disorders• spongiform degeneration
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Chronology
• XVIIIXVIII c. c. scrapiescrapie• 19201920 CJD (CJD (heritableheritable))• 19391939 scrapie scrapie transmissibletransmissible• 19541954 scrapie: „slow virus”scrapie: „slow virus”• 19591959 kuru kuru resemblesresembles CJD CJD• 19591959 kuru kuru resemblesresembles scrapie scrapie• 19661966 kuru kuru c chimpanzeehimpanzee transmissi transmissionon GAJDUSEKGAJDUSEK• 19821982 „prion” Prusiner„prion” Prusiner• 19861986 BSE (BSE (first case)first case)• 19971997 NobelNobel prize prize PRUSINERPRUSINER
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Ancient scrapie?
Wickner (2005) Science 309, 864
fleedisease = like rash
`
،
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Chronology
• XVIIIXVIII c. c. scrapiescrapie• 19201920 CJD (CJD (heritableheritable))• 19391939 scrapie scrapie transmissibletransmissible• 19541954 scrapie: „slow virus”scrapie: „slow virus”• 19591959 kuru kuru resemblesresembles CJD CJD• 19591959 kuru kuru resemblesresembles scrapie scrapie• 19661966 kuru kuru c chimpanzeehimpanzee transmissi transmissionon GAJDUSEKGAJDUSEK• 19821982 „prion” Prusiner„prion” Prusiner• 19861986 BSE (BSE (first case)first case)• 19971997 NobelNobel prize prize PRUSINERPRUSINER
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Stanley B. Prusiner
• strange pathogen (resistance to UV, heat etc…)
• purification
• transmission to mouse (incubation time 150-300 days)
• 1975-77: transmission to hamster (70 days)
P rPC
P rP sen P rP 2 7-3 0P rP res
P rPS C
1 2 32
infectedinfected
proteinproteinasease K K
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Infectious protein ?Infectious protein ?
• no DNA • PrPsc and infectivity purify together• properties of PrPsc match those of prion• PrP: encoded by the host• inherited forms: mutations of PrP gene
1982proteinaceous infectious
PRION
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Patholopgical prion: structure of PrPC
(PHGGGWGQ)5
A127GAAA*AGAVVGGLGG133
GPI
***
*
*
**
*
*P107L* P102L
Amyloid: mad-cow disease
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Extension of theExtension of the prion prion conceptconcept::
physiologicalphysiological prion prionss
Two yeastTwo yeast geneti genetic elementc element [[URE3URE3]], , [[PSI+PSI+]]
• domindominantant, n, nonon--Mendelian inheritanceMendelian inheritance (mei(meioois)is)• non-chnon-chromosromosomalomal (c (cyytoplatoplasmicsmic))• metastabmetastablele (curable) (curable)• sselective advantage ?elective advantage ?
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normnormalal Sup35p = Sup35p = [[psipsi--]]
prion Sup35p = prion Sup35p = [[PSIPSI++]]
Sup35p (translation release factor 3, eRF3)
Suppression Suppression of nof nonsensonsensee mutmutationsations
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Sup35p: eukaryotic translation release factor3
MSNPQDQLSNDLANASISGDQSKQPQQQQPQQQQPY
FNPNQAQAFVPTGGYQQFQPQQQQQYGGYQQNYTQY
QAGGYQQNYNNRGGYQQNYNNRGGYQQNYNNRGGYQ
QQQQQQYQAYNPNQQYGGYQAYNPQQQQQQQTQSQG
MSLADFQKQKAEQQASLNKPAVKKTLKLASSSGIKL
ANATKKVDTAKPAASKEASPAPKDEEASAEPEAKKE
STPVPASSSPAPAAADSTPAPVKKESTPTPSVASKS
APVSASASVVTADALAKEQEDEVDEEVVKDMFGGKD
HVSIIFMGHVDA........
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Prion (amyloid) form of Sup35 promotes translation read-through
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Sup35: disorder and modularity
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Sup35: disorder and modularity
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„„Lag-phase” Lag-phase” andand „seeding” „seeding” (1D crystal (1D crystal growth)growth)
Chen et al. (2001) JMB 311, 173
Long
incubation time
Exponential growth
„Seeding”
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Prion infection:Prion infection: „ „cross-cross-seeding”seeding”
Chen et al. (2001) JMB 311, 173
Long
incubation time
Exponential growth
„Cross-seeding”
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Extension of prion concept:
prions and memory?
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Hippocampus and memory
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Aplysia californica
habituation, sensitisation
LTF GSW reflex
Eric Kandel
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Aplysia neuronal CPEB is involved in LTF
5 x 5-HT
Si et al. (2004) Cell 115, 893
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Si et al. (2004) Cell 115, 879
Aplysia neuronal CPEB is a prion
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The structure of amyloid(ogenic) proteins
Needs to be addressed:Needs to be addressed:
- structure of amyloidogenic - structure of amyloidogenic proteinprotein
- structure of intermediate- structure of intermediate
- structure of amyloid itself- structure of amyloid itself
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Structure of amyloidogenic proteins
Globular:lysoyzme
transthyretin (TTR)
insulin
b2-microglobulin
IDP:-synuclein
tau protein
polyQ regions
prion domains
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Structure: lyslysozozyymmee
I56T
D67H
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Structure: pStructure: polyQolyQ
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Dedmon et al. (2005) JACS 127, 476
Structural ensemble of -synuclein
(NMR paramagnetic relaxation enhancement)
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Structure of amyloidogenic proteins
Globular:lysoyzme
transthyretin (TTR)
insulin
b2-microglobulin
IDP:-synuclein
tau protein
polyQ regions
prion domains
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Structure of amyloidogenic proteins
Globular: partial unfolding
lysoyzme
transthyretin (TTR)
insulin
b2-microglobulin
IDP: partial folding-synuclein
tau protein
polyQ regions
prion domains
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temp.temp.
Structure of the intermediate ?Structure of the intermediate ?
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Partially ordered amyloid precursors
Uversky and Fink (2005) BBA 1698, 131
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Wikipedia
SH3-PPII
The common denominator: polyproline II helix?The common denominator: polyproline II helix?
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PPII in a-synuclein PPII in a-synuclein (ROA)(ROA)
Syme (2002) EJB 269, 148
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57°C pH 2.0
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Structure of amyloid: cryo-EM
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A reasonable analogy: the Leu zipper
GCN-4 bZip
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Polar zipper (vs. Leu zipper)
Perutz (1994) Prot. Sci. 3, 1629
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Nelson et al. (2005) Nature 435, 773
Structure of Sup35 prion peptide (steric zipper)
DSNQGNNQQNYQQYSQNGNQQQGNNRYQGYQAYNAQAQPAGGYYQNYQGYSGYQQGGYQQYNPDAGYQQQYNPQGGYQQYNPQGGYQQQFNPQ
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Structure of A(beta) (1-40) protofilament
Luhrs (2005) PNAS 102, 16248
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Structural model of the CA150.WW2 Structural model of the CA150.WW2 protofilamentprotofilament
Ferguson (2006) PNAS 103, 162
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PPooints of interferenceints of interference
Dobson (2004) Science 304, 1259