4bTheNobelPrizeinChe mistry2004

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The Nobel Prize in Chemistry 2004:

The Nobel Prize in Chemistry 2004 96羅致宏 88鄭為遠 62陳昭佑 61陳建鴻 79劉郁軒 76楊曜鴻

名詞解釋:

名詞解釋

History&BackgroudofUbiquitin!!:

History&Backgroud of Ubiquitin!!

Slide6:

Aaron Ciechanover Birth:1947, Haifa, Israel 醫學博士任教於以色列工學院 Avram Hershko 1937出生任教於以色列工學院，與Aaron Ciechanover共事

Irwin Rose :

Irwin Rose 1926 目前在加州大學擔任教授

Background:

Background 蛋白質分解需要能量嗎? Trypsin&Lysosome 1950年，實驗發現蛋白質分解需要能量

History:

History 1975 Ubiquitin was first isolated from the thymus 1977 Goldberg 做了一個實驗 1978 Discovery of APF-1(ATP-dependent proteolysis factor 1) 1981~1983 Hershko&Ciechanover& Rose 分離出E1,E2和E3

Discovery of APF-1:

Discovery of APF-1 從網狀紅血球萃取 A small heat-stable polypeptide Divided by chromatography

為什麼需要UBQUITIN?:

為什麼需要UBQUITIN? 30%製造的蛋白質都會被分解提高分解效率

Introduction:

Introduction

What’s Ubiquitin?:

What’s Ubiquitin? Main role: become a “label” to target the substrate protein 死亡之吻 Protein degradation 蛋白質降解 Apoptosis: programmed cell death 最早命名為APF-1(ATP-dependent proteolysis factor 1)

結構:

結構 1977 Harris Goldknopf and Ira Busch DNA-associated 76 a.a 一個C端兩個N端 C端具有gly可與 protein substrate (最早在histone H2A)中的lys形成類肽鍵

Slide17:

E1:Ub-activating enzyme(需耗ATP) E2:Ub-conjugating enzyme E3:Ub-ligase

Ubiquination的放大:

Ubiquination的放大

兩種E3 Ubiquitin ligases:

兩種E3 Ubiquitin ligases HECT-domain proteins 先與Ub形成 thiol-ester bond 在其轉移到protein substrate前 RING finger proteins 帶領E2-ubiquitin complex至protein substrate E3是種complex

RING finger protein:

RING finger protein 一致的序列 8個Cys與His與Zn ion形成cross-braced fashion 有些獨立作用如Ubr1/E3α其他在complex中如SCF complex

PROTEASOME:

PROTEASOME A human cell contains about 30,000 proteasomes Barrel froemed Degrade proteins to 7~9a.a. polypeptides Active surface- inside The only way in to the active surface is via the "lock" The peptides formed are released from the other end of the proteasome. Proteasome cannot choose proteins, but E3 do it!

proteasome:

proteasome 蛋白酶體 for endogenous proteins (細胞內自我合成的)lysosome for extracellular proteins from endocytosis 可用來對抗improperly folded proteins

Slide26:

Alfred Goldberg (Harvard Med) & Martin Rechsteiner (Utah) in 1980's 90% of all abnormal, misfolded proteins Transcription factors

蛋白質的辨識”N-end rule”:

蛋白質的辨識”N-end rule” 在Protein substrate的N端有一特定,destabilizing的aa residue(來自post-translational modification) N-Degrons N端destabilizing residue Internal Lys (site for Ub attachment)

Slide29:

3 type of substrate Type I substrates are proteins that have a basic NH2-terminal residue (Arg, His, Lys) Type II substrates are proteins with bulky-hydrophobic N-termini (Leu, Trp, Phe, and Tyr) Type III substrates have Ser, Ala, and Thr residue E3α E3β

Ubiquitin並非唯一的tag:

Ubiquitin並非唯一的tag

Slide31:

Ubiquitin 與 cell cycle 之關聯

Cell cycle:

Cell cycle Ubiquitin-mediated proteolysis 控制了細胞週期中多數的細胞調節蛋白細胞週期為單一方向不可逆 Ub在各階段便有著解鎖的功能，使得細胞得以進入下一週期

如何將substrate標記?:

如何將substrate標記? Ub系統常會以single subunits 或 multiprotein complexes 來擔任需 Ubiquitinated的substrate的辨識因子在此以較龐大的Ubiquitin ligases中的 SCF complexes為例子

SCF complexes:

SCF complexes

SCF complexes:

SCF complexes 其中S 為 Skp1 ；C 為 Cul1 ；F 為 F-box protein 而FBP的組成直接影響了Substrate recognition

FBP之組成:

FBP之組成 FBP 基本是以40個a.a 的box(又稱為F-box)再以WD-40 或 leucine-rich repeats 等方式以增加其多樣性結果：得以讓SCF Complexe 能夠Ubiquitinate 多種不同的substrate

SCF 控制 cell cycle 之機制:

SCF 控制 cell cycle 之機制當兩種CDK inhibitors p21 及 p27 存在時，細胞會無法由 G1轉往 S 期此時便需要 SCFSkp2 來Ub化p21 及 p27

Slide38:

Skp2 和 Cks1 同為不穩定的蛋白質，如果沒預先被分解，細胞就會提早進入S期 APC/C (anaphase-promoting complex/cyclosome) 即為調節Skp2 和 Cks1的另一個Ub ligase

Slide39:

簡而言之：整個cell cycle是由多種Ub ligase所交互作用而成 ex : APC/C 和 SCF FBP ß-Trcp1 負責 Emi1(APC/C的抑制物的)的分解 Inactivation of the ß-Trcp1 造成老鼠胚胎纖維組織母細胞 Lengthened mitosis Centrosome overduplication Multipolar metaphase spindles Misaligned chromosomes

Slide40:

在許多人類癌症細胞中發現造成低含量的p27不是因為p27 gene的表現改變，而是過多不正常的Ub化的水解!! 造成細胞不正常增生 Carcinomas!! Low expression of p27

Ubiquitin and Diseases :

Ubiquitin and Diseases

Slide42:

What can go wrong in the UPS (Ubiquitin Proteasome System) to cause disorder and/or disease?

Human papilloma virus (HPV):

Human papilloma virus (HPV) What is HPV?

Human papilloma virus (HPV):

Human papilloma virus (HPV) What’s the relationship between HPV and Ub?

Huntinton’s disease(HD):

Huntinton’s disease(HD) 造成亨丁頓舞蹈症的基因是在第四對體染色體，與性別無關。 CAG序列重複次數較常人多症狀

UB & HD:

UB & HD

Conclusion:

Conclusion

未來展望:

未來展望 UB是一個很新的研究未來可望從這方面找出cancer、HD等疾病的治療方法

在這堂課要你學會的是:

在這堂課要你學會的是 UB是什麼?? Protein的degradation UB影響的層面

THANKS!!:

THANKS!!

4bTheNobelPrizeinChe mistry2004

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Presentation Transcript

The Nobel Prize in Chemistry 2004:

名詞解釋:

History&Backgroud of Ubiquitin!!:

Slide6:

Irwin Rose :

Background:

History:

Discovery of APF-1:

為什麼需要UBQUITIN?:

Introduction:

What’s Ubiquitin?:

結構:

Slide17:

Ubiquination的放大:

兩種E3 Ubiquitin ligases:

RING finger protein:

PROTEASOME:

proteasome:

Slide26:

蛋白質的辨識”N-end rule”:

Slide29:

Ubiquitin並非唯一的tag:

Slide31:

Cell cycle:

如何將substrate標記?:

SCF complexes:

SCF complexes:

FBP之組成:

SCF 控制 cell cycle 之機制:

Slide38:

Slide39:

Slide40:

Ubiquitin and Diseases :

Slide42:

Human papilloma virus (HPV):

Human papilloma virus (HPV):

Huntinton’s disease(HD):

UB & HD:

Conclusion :

未來展望:

在這堂課要你學會的是:

THANKS!!:

History&BackgroudofUbiquitin!!:

Conclusion: