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The Nobel Prize in chemistry 2004

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. Israel Aaron Ciechanover. USA Irwin Rose. Israel Avram Hershko. http://big5.cctv.com/science/20041008/101027.shtml. The Discovery of The Ubiquitin.

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The Nobel Prize in chemistry 2004

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  1. 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

  2. Nobel Laureate Israel Aaron Ciechanover USA Irwin Rose Israel Avram Hershko http://big5.cctv.com/science/20041008/101027.shtml

  3. The Discovery of The Ubiquitin • simple protein-degrading enzymes • Trypsin • Lysosome Traditional concept do not require energy

  4. Paradox • 1950s－the breakdown of the cell's proteins require energy • The inhibitor of lysosome has no effect on some protein degradation • Rabbit reticulocytes (網織紅血球) degrade abnormal hemoglobin

  5. 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

  6. The Discovery of The Ubiquitin • ATP-dependent proteolysis factor 1 (APF-1) • 1981～1983－enzyme systems that binds ubiquitin to target proteins • multistep ubiquitin-tagging hypothesis

  7. Poly Ub : Ub-proteasome pathway For protein (peptide) recycling Decomposition( proteasome ) The kiss of death Mono Ub: non-degradation Modification(methylation of Histone) The Function of Ubiquitin Ub Ub Ub Ub Target protein Target protein

  8. The structure of Ubiquitin http://www.nottingham.ac.uk/biochemcourses/students/ub/ubindex.html A 76 a. a. protein Stable: O H Highly conserved Exist in archeabacteria and all eukaryotes

  9. Binding Lysine target protein Ub • target protein • Ub’s C-terminus the target protein’s Lysine • Form isopeptide

  10. Poly-ubiquitinization Protein 1 Ub Ub Ub Protein 2 Ub Ub Ub Ub Ub Ub’s C-terminus Ub’s lysine Purpose: recognize diversity protein

  11. L48 vs.L63 Ub Ub Ub Ub Degraded by proteasome L48 Target protein Ub Ub Ub Ub Degraded by lysosome L63 Target protein

  12. Other lysine site(human’s Ub ) 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

  13. Ub-Proteasome Pathway http://www.bio-pro.de/imperia/md/images/grafiken/ubisystem_338x398.jpg

  14. E2 Ubiquitnation • Remarkable features • The specificity of protein tagging is mainly determined by E2, E3 • steps • E1:Ub-activating enzyme • E2:Ub-conjugating enzyme • E3:Ub-ligase

  15. Adenylation Ub adenylate AMP ATP Cysteine E1 Activation Ub E1:Ub-activating enzyme C-terminus Cysteine S-H

  16. Ub adenylate AMP E2 E1 1.Connection of polyUb 2.Elongation of Ub with E3 E3 Ub Ub Ub E2:Ub-conjugating enzyme New S-H

  17. E3 E3 E3 Recognition of the substrate E3 E3:Ub-ligase • Two types • E3s which do form thiol esters with ubiquitin • E3s which do not form thiol esters with ubiquitin. From:www.wormbook.org/.../ubiquitinpathways.html

  18. Proteasome • Barrel-like structure • Degrade ubiquinated protein • Use the energy of ATP

  19. Structure • Core protease particle (CP) • Catalytic area • Regulatory particle (RP) • Ubquitin recognition • Deubiquitin • ATPase α β β α http://www.bioscience.utah.edu/mb/mbFaculty/hill/hill.html

  20. http://www.bio-pro.de/imperia/md/images/grafiken/ubisystem_338x398.jpghttp://www.bio-pro.de/imperia/md/images/grafiken/ubisystem_338x398.jpg

  21. Ubiquitin and p53 • Tumor suppressor gene • DNA repair • Apoptosis

  22. Cancer reason：HPV • Human Papillomavirus • Activate E6-AP(E3) to ubiquitinate p53 • Few P53 • Dysplasia

  23. Medicine • LDP-341 (PS-341) • Proscript invented in 1995 • Inhibit ubiquitin • function • Retain cyclin • Inhibit NF-kappa B • Protein pressure

  24. Spinocerebellar Atrophy(小腦萎縮症) • Background detail • Cause of disease- gene • Symptom • 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)

  25. 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

  26. SUMO SUMO SUMO SUMO Abnormal protein Abnormal protein Abnormal protein Abnormal protein Abnormal SUMO In Spinocerebellar Atrophy Finally cell death Ub Abnormal protein SUMO

  27. Parkinson’s Disease(帕金森氏症) Background detail • Cause of disease- gene • Symptom • Nervous system: death of basal ganglia (基底核)and substantia nigra (黑質) cell • Behavior: tremor；rigidity • Dopamine(多巴胺) • Reason (related to ubiquitin) • Abnormal α-synuclein gene • Abnormal parkin(E3) gene

  28. Ub E2 Abnormal parkin(E3) Ub Ub Ub Abnormal α-synuclein protein Abnormal α-synuclein protein Abnormal α-synuclein protein Abnormal α-synuclein gene Abnormal parkin(E3) gene Finally cell death Abnormal protein Ub Abnormal α-synuclein protein Finally cell death

  29. 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 Ub • E2:regulating poly-ubiquitinization • E3:recognition of substrates

  30. Take Home Messages • Mechanism of P53,HPV, Spinocerebellar Atrophy and Parkinson’s Disease are all related to the ubquitination, especially the function of E3.

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