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研究生:趙需文
研究生(外文):Hsu-Wen Chao
論文名稱:SUMO修飾MAGUK蛋白CASK並調控神經細胞樹突上突觸之形成
論文名稱(外文):SUMOylation of The MAGUK Protein CASK Regulates Dendritic Spinogenesis
指導教授:薛ㄧ蘋
指導教授(外文):Yi-Ping Hsueh
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:英文
論文頁數:146
中文關鍵詞:神經細胞突觸小泛素
外文關鍵詞:CASKSUMOneuronspine
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神經細胞突觸形成是需要透過細胞間前後突觸區域以及細胞內蛋白分子交互作用和精細的調控而完成。部份MAGUK家族蛋白成員已經被認為會聚集在突觸區域,透過作為分子骨架的功能來幫助突觸膜蛋白和訊號蛋白間的交互作用,並且調控神經細胞的功能。CASK是屬於MAGUK蛋白家族的其中ㄧ員。目前已知道CASK基因的突變和人類X染色體連鎖智能遲滯的發生有密切關聯。此外,將CASK基因剔除之後,其小鼠會在出生後24小時內死亡,並且造成神經細胞在電生理上的異常表現。本篇論文,為了要探討CASK在神經突觸上的功能,首先利用專一的shRNA抑制神經細胞內的CASK蛋白生成,同時配合time-course的實驗發現到CASK會藉由影響突觸的穩定性而影響突觸的形成。此外利用特定蛋白片段大量表現在神經細胞,以干擾CASK訊息傳遞時可以發現到,CASK是可以透過syndeca-2和蛋白質4.1訊息路徑來調控突觸的形成。由進ㄧ步的實驗我們更發現到,CASK在其蛋白序列lysine 679會被小泛素 (SUMO1) 所修飾。而lysine 679非常靠近與蛋白質4.1結合的位置。實驗結果顯示,小泛素對CASK的修飾確實會影響到CASK和蛋白質4.1之間的交互作用,因此影響到CASK和細胞骨架蛋白actin的結合。若進ㄧ步的將CASK-SUMO1結合蛋白表現在神經細胞時,則會發現到突觸的形成會受到影響。因此,由實驗的結果可以推測,CASK可以被小泛素蛋白所修飾,藉由修飾的過程CASK可以進行調控突觸膜蛋白和細胞骨架actin之間的聯結以及穩定性,並由此更進ㄧ步的調控突觸的形成。
Spinogenesis is a process requiring both intercellular molecules interaction and intracellular signaling regulation in synaptic region. Membrane-associated guanylate kinase (MAGUK) family proteins, the synaptic scaffold proteins, interact with synaptic membrane and cytoplasmic proteins, and thus regulate synaptic interaction and functions. One of the MAGUK proteins, CASK has been reported to directly involve in X-link mental retardation in humans. Moreover, other report suggests that deletion of CASK in mice is lethal and impairs synaptic functions. In this study, CASK shRNA was applied to evaluate the function of CASK protein during spinogenesis. Results of the time-course experiment showed that CASK was required for spinogenesis and contributed to the maintenance of spine morphology. The domain deletion analysis revealed that CASK may link to both transmembrane adhesion molecules and actin cytoskeleton, and thus facilitated spinogenesis. Furthermore, we found that CASK can be modified post-translationally by SUMO1 conjugation at the lysine 679 residue near the protein 4.1N binding motif. SUMOylation of CASK interrupted the interaction of CASK and protein 4.1, thus, reduced the association between CASK and actin cytoskeleton. Overexpression of a CASK-SUMO1 fusion constructs, which mimic SUMOylated CASK, impaired dendritic spine formation. In conclusion, we demonstrated that CASK regulates spinogenesis through its PDZ and protein 4.1 binding domain. Furthermore, SUMOylation of CASK interferes the binding of CASK to proein 4.1 and actin. Therefore, we hypothesized that CASK can act as a linker to stabilize the connection of synaptic membrane and actin cytoskeleton, and SUMOylation of CASK impairs spinogenesis.
CONSTANTS
中文摘要…………………………………………………………….…….…………1
ABSTRACT……………………………………………………………. ……………2
INTRODUCTION…………………………………………………………………….3
1. Nueronal Development……………………………….………………...………3
1.1 Development of Brain…………..….………..……………..…………….3
1.2 Neuron Morphogenesis…………….…………….………..……….……4
1.3 Spinogenesis and Synaptogenesis………………..…….…………..…6
2. CASK (Calcium/calmodulin-dependent serine protein kinase)…………..10
2.1 Family of MAGUK Proteins…….….…………….……..…...…………10
2.2 The Structure of CASK………………...…….……………..………..…12
2.2-1 The CASK CaMK-Like domain.……………………..…..………12
2.2-2 The CASK LIN2/LIN7 (L27) domain……………..……...………14
2.2-3 The CASK PDZ domain…………………………………….……14
2.2-4 The CASK SH3 domain…………………………………….……15
2.2-5 The CASK Protein 4.1 binding domain…………………………16
2.2-6 The CASK GK domain………………………………..…….……17
2.3 The Biological Functions of CASK…………………..…….…….…….17
2.3-1 CASK and brain development……………….……….………….17
2.3-2 Trafficking of targeting proteins…………….……………..…….18
2.3-3 Spines formation and synaptogenesis……….…….….……….19
2.3-4 The nuclear function of CASK……….………………….……….21
2.4 Genetic Diseases………………….………..………..…..…….……….24
2.4-1 Genetic mouse models…….………..………..……...….……….24
2.4-2 CASK gene mutation in human……..………………….……….24
3. SUMOs (Small Ubiquitin-like Modifiers)….…………….……….………….26
3.1 The Family of Small Ubiquitin-like Midifiers……………………….….26
3.2 SUMOs conjugation and deconjugation pathway……………...…….28
3.3 Biological functions of SUMOs……………….….………….…..…..…32
MATERIAL AND METHODS………………..………….……………..………….37
Reagents and Solutions……………...…………….……………….….……….37
Methods……..…………………………………………………….……………..54
SPECIFIC AIMS……………………………………………………………………69
RESULTS…………………………………………………………………………..70
CASK is required for spinogenesis………………………..…………………..70
The PDZ domain and protein 4.1 binding site of CASK are involved in spine formation…………………………………………………………………..….….72
CASK proteins are SUMOylated……………………………….………………75
SUMOylated CASK proteins are presented at synapses……………………77
CASK SUMOylation impairs the binding of CASK to protein 4.1 and actin cytoskeleton………………………………………………………...……………81
SUMOylation of CASK influences spine morphogenesis……………………83
DISCUSSIONS………………………….……………………………….…………86
Collaboration of CASK PDZ and SH3 domain and spinogenesis……….….87
CASK and spine maintenance…………………………………………………88
The function of CASK and SUMO1 at presynaptic site……………..….……89
CASK shRNA and KO mice…………………………………………….………92
The effect of SUMO1 on CASK and neurons……………………….…..……93
Other functions of SUMOylation CASK……………………………….………95
REFERENCE………………………………………………………………….……99
FIGURES………………………………………………………………….…….…111
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