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研究生:郭佳雯
研究生(外文):Jia-Wen Guo
論文名稱:APP結合蛋白質1與脯胺酸異構酶Pin1對beta-Amyloid前驅蛋白質的交互作用與調節
論文名稱(外文):Interaction and Regulation of beta-Amyloid Precursor Protein by APPBP1 and Pin1
指導教授:呂佩融
學位類別:碩士
校院名稱:國立中山大學
系所名稱:生物醫學科學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:126
中文關鍵詞:交互作用調節蛋白質
外文關鍵詞:pin1regulationinteractonAPPBP1beta-amyloid precursor protein
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b-Amyloid (Ab) 所形成的senile plaques被認為是造成Alzheimer’s disease (AD) 的原因之一,也是AD之一個重要病理徵象,但目前對於Ab的沈積與Alzheimer’s disease之間的關係仍是不完全清楚的。Ab來自一個前驅蛋白質,稱為b-Amyloid precursor protein (APP) ,當APP經b secretases和g secretases切割後,可釋出Ab,然而APP的正常生理功能亦尚未定論。結構分析APP為type I transmembrane protein,N-terminus朝向細胞膜外,含有兩個glycosylation sites,可經由轉譯後修飾的作用進行N-glycosylation及O-glycosylation,此過程與APP的maturation有關;C-terminus則位於細胞膜內,不但含有三個可被磷酸化的位置 (Thr654,Ser655及Thr668,數字參照APP695) ,並且包含數個具功能性的保留性序列,這些保留性序列已被證明可與特定的蛋白質進行交互作用,因而APP的C-terminus (APPC) 被認為可能與細胞訊息傳遞有關。APP binding protein 1 (APPBP1) 可與APP的C-terminus結合,研究指出APPBP1是S-M checkpoint之調節者,為參與細胞分裂不可缺少的因子,然而目前對APPBP1在細胞內的分佈及其生理功能仍不完全清楚。蛋白質的磷酸化作用常會影響蛋白質的構形與其他分子的結合能力。研究指出APPC的三個磷酸化位置以Thr668被磷酸化後所造成構形的改變最為顯著,這是因為Pro669之cis / trans isomerization所造成的構形上的影響;此生理意義亦待進一步的研究。Ser / Thr Pro motif為Cdc2在受質上所磷酸化的位置,而APPC之Thr668及Pro669已被證明為Cdc2 的磷酸化位置。加上目前研究顯示在Alzheimer’s disease的腦部組織中發現有不正常的mitotic events產生,伴隨大量mitotic proteins表現增加的情形,其中Cdc2亦不正常地被活化在AD brain,而被認為與神經元細胞的死亡和AD的致病機制可能有密切的關係。另一方面Cdc2磷酸化Thr668對於調控APP正常的生理功能與其代謝亦可能扮演重要的角色,但其產生何種訊息傳導仍是未知的。Pin1,是一個重要的mitotic regulator,本實驗室初步證明Pin1只能與mitotic phase時的APP進行interaction (Kd為20 nM) 。由於Pin1為peptidyl-prolyl cis / trans isomerases,其與APP的結合意涵著某種生化活性的調控。在本研究中我們獲得以下結果: (1) APPC及APPBP1皆可表現在細胞質與細胞膜: (2) 無論是in vivo或in vitro,APPC皆可與APPBP1結合;(3) Thr668為APP唯一之Cdc2 phosphorylation site;(4) 當APPBP1結合至APPC時影響Cdc2磷酸化APPC;(5) APP之Thr668的磷酸化可減低與APPBP1或Pin1的結合;(6) APPC為caspase 3的受質;(7) APPC之Thr668磷酸化調控caspase 3 activity;(8) APPBP1或Pin1與APPC的結合可調控caspase 3 activity。
b-amyloid is derived from amyloid precursor protein (APP) and tightly associated with the pathogenesis of Alzheimer’s disease (AD). Structurally, APP belongs to type I transmembrane protein family and is composed of a large glycosylated extracellular component, a single membrane-spanning region, and a short cytoplasmic domain. Although physiological function of APP remains unclear, the proteolytic processing of APP by b secretase and g secretase gives rise to the production and secretion of b-amyloid. The C-terminus of APP is believed to participate in the intracellular trafficking of APP and signal transduction via interacting with adaptors and signaling proteins, respectively. Three phosphorylation sites (Thr654, Ser655 and Thr668, numbering for APP695 isoform) and several functional motifs in the cytoplasmic domain of APP have been identified and demonstrated that the phosphorylation can indeed affect APP metabolism including: the rate of secretion, endocytosis and b-amyloid production. In this study, we focused on how APP binding protein1 and the phosphorylation affect on APP metabolism. The reasons are as following: (1) Among many APP associated proteins, APP binding protein 1 (APPBP1) is involved in S-M checkpoint regulation. (2) Recent evidence indicates that aberrantly activation of mitotic events may play an important role in development of AD. Since progression through mitosis is regulated by Cdc2 that has been demonstrated to phosphorylate APP on Thr668-Pro669, the phosphorylation of APP at Thr668 may play the important role in regulating APP metabolism and may also relate to AD development. (3) Moreover, protein phosphorylation induces the conformational change and affects the protein- protein interaction. Phosphorylation of Ser / Thr-Pro motif is a central mechanism controlling progression of the cell cycle, including mitosis. Proline residues provide a potential backbone switch in the polypeptide chain controlled by the cis / trans isomerization. Pin1 is an important mitotic regulator and a highly specific peptidyl-prolyl cis / trans isomerases (PPIase) that catalyzes the isomerization of phosphorylated Ser / Thr-Pro bonds. Our unpublished data have shown that Pin1 can bind to the phosphorylated Thr668-Pro669 APP peptide with high affinity (20 nM) that suggested that Pin1 may interact and regulate mitotic APP. Taken together, these data suggested that the interaction of APP and APPBP1 or Pin1 may affect the APP metabolism and its physiological function. This study investigated the hypothesis above and revealed includes the following results (i) the subcellular localization of the C-terminus of APP and APPBP1; (ii) the interaction between APPBP1 and the C-terminus of APP in vivo and in vitro; (iii) Thr668 of APP is the Cdc2 phosphorylation site; (iv) the binding of APPBP1 to the C-terminus of APP reduces the phosphorylation of APP by Cdc2; (v) the phosphorylation at Thr668 can abolish the interaction between APPBP1 and the C-terminus of APP; (vi) the C-terminus of APP is one of the caspase 3 targets; (vii) the phosphorylation of APP at Thr668 also reduces the caspase 3 activity forward to the C-terminus of APP cleavage; (viii) both APPBP1 and Pin1 can inhibit the C-terminus of APP cleavage by caspase 3 that suggested two novel mechanisms to regulate APP metabolism.
目錄
中文摘要…………………………………………………….…………..…i
英文摘要…………………………………………………………..……....iv
英文縮寫表………………….………………….………………..…..…...vii
緒論…………………………………….………………….………………1
材料與方法……………………………….………………………………13
結果…………………….………………….………………….…………..46
討論…………………………..……………….………………….……….56
參考文獻…………………….……………….…………………………...63
圖解……………………………………………….………………………77
圖……………………….…………………………………………………85
表……………………….……………………….…..…………………..104
附錄……………………….……………………….……………………106
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