the nobel prize in chemistry 2004 ubiquitin(ub) 泛素 class b group 3...
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The Nobel Prize in chemistry 2004
Ubiquitin(Ub)泛素
Class B Group 3黃恒橋、劉國正、黃偲媁黃竣聖、簡農軒、楊昆霖
Nobel Laureate
IsraelAaronCiechanover
IsraelAvramHershko
USA
Irwin
Rosehttp://big5.cctv.com/science/20041008/101027.shtml
The Discovery of The Ubiquitin
simple protein-degrading enzymes TrypsinLysosome
do not require energy
Traditional concept
Paradox 1950s - the breakdown of the cell's prot
eins require energy
The inhibitor of lysosome has no effect on some protein degradation
Rabbit reticulocytes ( 網織紅血球 ) degrade abnormal hemoglobin
The Discovery of The Ubiquitin
1975 - isolated Ub from sweetbread
( 小牛胸腺 ) 1977 - an extract from reticulocytes 1970s ~ 1980s - the extract could be
divided into two fractions Fxn1 Fxn2
The Discovery of The Ubiquitin
ATP-dependent proteolysis factor 1 (APF-1) 1981 ~ 1983 - enzyme systems that bin
ds ubiquitin to target proteins
multistep ubiquitin-tagging hypothesis
Poly Ub : Ub-proteasome pathway For protein (peptide) recyclingDecomposition( proteasome ) The kiss of death
Mono Ub: non-degradationModification(methylation of Histone)
The Function of Ubiquitin
Target protein
UbUb
Target protein
UbUbUbUbUbUb
The structure of Ubiquitin
A 76 a. a. protein Stable: O H Highly conserved Exist in archeabacte
ria and all eukaryotes
http://www.nottingham.ac.uk/biochemcourses/students/ub/ubindex.html
Binding
target proteinUb’s C-terminus the target protein’
s LysineForm isopeptide
target protein
Lysine
UbUb
Poly-ubiquitinization
Ub’s C-terminus Ub’s lysine Purpose: recognize diversity protein
Protein 1
Protein 2
UbUb UbUb
UbUb UbUbUbUbUbUb
UbUb
UbUb
Target protein
Target protein
L48 vs.L63
UbUbUbUbUbUbUbUb
UbUbUbUbUbUbUbUb
L48
L63
Degraded by proteasome
Degraded by lysosome
Met1-Gln2-Ile3-Phe4-Val5-Lys6-Thr7-Leu8-Thr9-Gly10-Lys11-Thr12-Ile13-Thr14-Leu15-Glu16-Val17-Glu18-Pro19-Ser20-Asp21-Thr22-Ile23-Glu24-Asn25-Val26-Lys27-Ala28-Lys29-Ile30-Gln31-Asp32-Lys33-Glu34-Gly35-Ile36-Pro37-Pro38-Asp39-Gln40-Gln41-Arg42-Leu43-Ile44-Phe45-Ala46-Gly47-Lys48-Gln49-Leu50-Glu51-Asp52-Gly53-Arg54-Thr55-Leu56-Ser57-Asp58-Tyr59-Asn60-Ile61-Gln62-Lys63-Glu64-Ser65-Thr66-Leu67-His68-Leu69-Val70-Leu71-Arg72-Leu73-Arg74-Gly75-Gly76
Other lysine site(human’s Ub )
Ub-Proteasome Pathway
http://www.bio-pro.de/imperia/md/images/grafiken/ubisystem_338x398.jpg
Ubiquitnation
Remarkable features The specificity of protein tagging is
mainly determined by E2, E3 steps
E1:Ub-activating enzymeE2:Ub-conjugating enzymeE3:Ub-ligase
E2
E1:Ub-activating enzyme
E1
AMP Ub
S-H
ATP
Ub adenylate CysteineAdenylation
C-terminus
Cysteine
Activation
E2:Ub-conjugating enzyme
E2
AMP
Ub adenylate
Ub Ub Ub
E1S-HNew
E3
1.Connection of polyUb
2.Elongation of Ub with E3
E3:Ub-ligase
Two types
E3s which do form thiol esters
with ubiquitin
E3s which do not form thiol esters with ubiquitin.
E3
E3
E3
E3
From:www.wormbook.org/.../ubiquitinpathways.html Recognition of the substrate
Proteasome
Barrel-like structure
Degrade ubiquinated protein
Use the energy of ATP
Structure
Core protease particle (CP)Catalytic area
Regulatory particle (RP)Ubquitin recogniti
onDeubiquitinATPase
http://www.bioscience.utah.edu/mb/mbFaculty/hill/hill.html
α
β
β
α
http://www.bio-pro.de/imperia/md/images/grafiken/ubisystem_338x398.jpg
Ubiquitin and p53
Tumor suppressor gene DNA repair Apoptosis
Cancer reason : HPV
Human Papillomavirus Activate E6-AP(E3) to ubiquitinate p53 Few P53 Dysplasia
Medicine
LDP-341 (PS-341) Proscript invented in 1995 Inhibit ubiquitin function
Retain cyclinInhibit NF-kappa BProtein pressure
Spinocerebellar Atrophy( 小腦萎縮症 )
Background detail Cause of disease- geneSymptom
nervous system: cell death Behavior: paralysis
One of causes- ” inclusion bodies “( 包涵體 )
Proteins are combined by SUMO-1 SUMO(Small ubiquitin-like modifier)
SUMO( 類泛素 )
Small ubiquitin-like modifier Function: Modification
Proteins linked by Ub or SUMO could be recognized by cell and be sent to different organelles.
Threat
Abnormal SUMO In Spinocerebellar Atrophy
Abnormal proteinSUMO
Ub
Abnormal protein
SUMO
Abnormal protein
SUMOAbnormal protein
SUMO
Abnormal protein
SUMO
Finally cell death
Parkinson’s Disease( 帕金森氏症 )
Background detailCause of disease- geneSymptom
Nervous system: death of basal ganglia ( 基底核 )and substantia nigra ( 黑質 ) cell
Behavior: tremor ; rigidityDopamine( 多巴胺 )
Reason (related to ubiquitin)Abnormal α-synuclein geneAbnormal parkin(E3) gene
Abnormal α-synuclein proteinUb
Abnormal
α-synuclein gene
Abnormal
parkin(E3) gene
Finally cell death
Finally cell death
Abnormal parkin(E3)
Abnormal protein
Abnormal α-synuclein protein
UbAbnormal α-synuclein protein
Ub
Abnormal α-synuclein protein
Ub
E2
Ub
Take Home Messages
Ub target substrates for degradation, traffic, or modification. The well-known function is involving ubiquitin proteasome system(UPS).
Ubiquitination has to be aided by E1:activating UbE2:regulating poly-ubiquitinizationE3:recognition of substrates
Take Home Messages
Mechanism of P53,HPV, Spinocerebellar Atrophy and Parkinson’s Disease are all related to the ubquitination, especially the function of E3.