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
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
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 ???
Amyloid fibrils
• 10 nm
• straight
• stable
• tinctorial properties (Congo red)
• cross-b
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
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
1) Protein (AL, ATTR, ALys)
2) Cause (spontaneous, mutation, induced)
3) Mechanism (loss or gain of function)
Amyloid diseases: modern classification
protein misfolding diseases
AD plaque Neurofibrillary tangle (PHF)
Alzheimer’s disease
Amyloid precursor protein (APP)
(TACE, ADAM10)
(PSEN)
„Lag-phase” and „seeding” (1D crystal growth)
Chen et al. (2001) JMB 311, 173
Long
incubation time
Exponential growth
„Seeding”
Familial systemic amyloidosis:
LLysysozozyymmee mut mutantsants
I56T
D67H
Reduced stability of amyloidogenic mutants
Wild type
Ile56Thr
Asp67His
Booth et al. (1997) Nature 385, 787
normal
kidney
liver
123I-SAP scintigraphy
Pepys
Huntington’s disease (Huntingtin)
MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQPLLPQPQPPPPPPPPPPGPAVAEEPLHRPKKELSATKKDRVNHCLTICENIVAQSVRNSPEFQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKALMDSNLPRLQLELYKEIKKNG…
ATGGCGACCCTGGAAAAGCTGATGAAGGCCTTCGAGTCCCTCAAGTCCTTCCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAACAGCCGCCACCGCCGCCGCCGCCGCCGCCGCCTCCTCAGCTTCCTCAGCCGCCGCCGCAGGCACAGCCGCTGCTGCCTCAGCCGCAGCCGCCCCCGCCGCCGCCCCCGCCGCCACCCGGCCCGGCTGTGGCTGAGGAGCCGCTGCACCGACCAAAGAAAGAACTTTCAGCTACCAAGAAAGACC…
PolyQ expansion: polymorphisms
Wells (1996) JBC 271, 2875
Huntingtin inclusions in neuronal nuclei
Perutz (1999) TiBS 24, 58
Cause of disease?
Loss of function
Gain of function
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
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
• rapid cognitive impairment (dementia)• movement disorders• spongiform degeneration
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
Ancient scrapie?
Wickner (2005) Science 309, 864
fleedisease = like rash
`
،
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
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
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
Patholopgical prion: structure of PrPC
(PHGGGWGQ)5
A127GAAA*AGAVVGGLGG133
GPI
***
*
*
**
*
*P107L* P102L
Amyloid: mad-cow disease
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 ?
normnormalal Sup35p = Sup35p = [[psipsi--]]
prion Sup35p = prion Sup35p = [[PSIPSI++]]
Sup35p (translation release factor 3, eRF3)
Suppression Suppression of nof nonsensonsensee mutmutationsations
Sup35p: eukaryotic translation release factor3
MSNPQDQLSNDLANASISGDQSKQPQQQQPQQQQPY
FNPNQAQAFVPTGGYQQFQPQQQQQYGGYQQNYTQY
QAGGYQQNYNNRGGYQQNYNNRGGYQQNYNNRGGYQ
QQQQQQYQAYNPNQQYGGYQAYNPQQQQQQQTQSQG
MSLADFQKQKAEQQASLNKPAVKKTLKLASSSGIKL
ANATKKVDTAKPAASKEASPAPKDEEASAEPEAKKE
STPVPASSSPAPAAADSTPAPVKKESTPTPSVASKS
APVSASASVVTADALAKEQEDEVDEEVVKDMFGGKD
HVSIIFMGHVDA........
Prion (amyloid) form of Sup35 promotes translation read-through
Sup35: disorder and modularity
Sup35: disorder and modularity
„„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”
Prion infection:Prion infection: „ „cross-cross-seeding”seeding”
Chen et al. (2001) JMB 311, 173
Long
incubation time
Exponential growth
„Cross-seeding”
Extension of prion concept:
prions and memory?
Hippocampus and memory
Aplysia californica
habituation, sensitisation
LTF GSW reflex
Eric Kandel
Aplysia neuronal CPEB is involved in LTF
5 x 5-HT
Si et al. (2004) Cell 115, 893
Si et al. (2004) Cell 115, 879
Aplysia neuronal CPEB is a prion
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
Structure of amyloidogenic proteins
Globular:lysoyzme
transthyretin (TTR)
insulin
b2-microglobulin
IDP:-synuclein
tau protein
polyQ regions
prion domains
Structure: lyslysozozyymmee
I56T
D67H
Structure: pStructure: polyQolyQ
Dedmon et al. (2005) JACS 127, 476
Structural ensemble of -synuclein
(NMR paramagnetic relaxation enhancement)
Structure of amyloidogenic proteins
Globular:lysoyzme
transthyretin (TTR)
insulin
b2-microglobulin
IDP:-synuclein
tau protein
polyQ regions
prion domains
Structure of amyloidogenic proteins
Globular: partial unfolding
lysoyzme
transthyretin (TTR)
insulin
b2-microglobulin
IDP: partial folding-synuclein
tau protein
polyQ regions
prion domains
temp.temp.
Structure of the intermediate ?Structure of the intermediate ?
Partially ordered amyloid precursors
Uversky and Fink (2005) BBA 1698, 131
Wikipedia
SH3-PPII
The common denominator: polyproline II helix?The common denominator: polyproline II helix?
PPII in a-synuclein PPII in a-synuclein (ROA)(ROA)
Syme (2002) EJB 269, 148
57°C pH 2.0
Structure of amyloid: cryo-EM
A reasonable analogy: the Leu zipper
GCN-4 bZip
Polar zipper (vs. Leu zipper)
Perutz (1994) Prot. Sci. 3, 1629
Nelson et al. (2005) Nature 435, 773
Structure of Sup35 prion peptide (steric zipper)
DSNQGNNQQNYQQYSQNGNQQQGNNRYQGYQAYNAQAQPAGGYYQNYQGYSGYQQGGYQQYNPDAGYQQQYNPQGGYQQYNPQGGYQQQFNPQ
Structure of A(beta) (1-40) protofilament
Luhrs (2005) PNAS 102, 16248
Structural model of the CA150.WW2 Structural model of the CA150.WW2 protofilamentprotofilament
Ferguson (2006) PNAS 103, 162
PPooints of interferenceints of interference
Dobson (2004) Science 304, 1259