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研究生:蕭丞志
研究生(外文):Cheng-Chih Hsiao
論文名稱:EGF-TM7受體的G蛋白聯繫受體溶解點其自我蛋白質溶解受到N-醣苷化作用調節
論文名稱(外文):The G protein-coupled receptor proteolytic site (GPS) autoproteolysis in EGF-TM7 receptors is modulated by N-glycosylation
指導教授:林錫賢
指導教授(外文):Hsi-Hsien Lin
學位類別:碩士
校院名稱:長庚大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:英文
論文頁數:88
外文關鍵詞:GPCRLNB-TM7EGF-TM7EMR2CD97GPS autoproteolysisN-glycosylationsite-directed mutagenesis
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LNB-TM7分子的N端有很長的細胞外結構 (extracellular domain),大部分的LNB-TM7分子會藉由一個似黏蛋白 (mucin-like)區域上的G蛋白連繫受體蛋白溶解點 (G protein coupled receptor proteolysis site, GPS)進行獨特的轉釋後蛋白溶解作用後,再連接至七次穿膜結構 (7TM)上;基於它們的特殊結構,LNB-TM7分子被認為具有可以與其他細胞表面蛋白或細胞外間質蛋白互相作用的功能,並經由七次穿膜結構產生細胞內的訊息傳導,LNB-TM7分子的重要性已經在某些人類疾病如Usher syndrome type II 及bilateral frontoparietal polymicrogyria (BFPP)中証實,同時GPS位置的蛋白溶解與LNB-TM7 分子的特殊功能有著重要的關係。但是,截至目前為止我們對G蛋白聯繫受體溶解點其自我蛋白質溶解的調控機制還不清楚。
EGF-TM7是LNB-TM7 家族中的成員,其特色為細胞外結構由似上皮生長因子區域組成,比較EMR2和CD97 兩個序列十分相近的EGF-TM7分子,發現EMR2蛋白溶解效率接近95%,但是CD97只有約50%;透過一連串的區域互換,證實似黏蛋白區域和G蛋白連繫受體蛋白溶解點對於控制G蛋白連繫受體蛋白溶解點的蛋白質溶解扮演很重要的角色。之後,使用N-醣苷化抑制劑來處理表現EMR2-mFc和CD97-mFc的細胞發現蛋白質的自我蛋白質溶解效率減少,這個結果證明N-醣苷化作用調控G蛋白聯繫受體溶解點的自我蛋白質溶解;同時還發現EGF-TM7自我蛋白質溶解發生在寡聚糖前趨體連接到蛋白質的步驟上,與N-醣苷化作用的後期過程無關。我們建立CD97不同的N-醣苷化位置的特殊位置突變體,發現G蛋白聯繫受體溶解點的自我蛋白質溶解會被特殊位置N-醣苷化具體影響。
我們的研究證明似黏蛋白區域和其上的N-醣苷化會影響受器的蛋白質摺疊以及GPS 蛋白溶解,進一步提出一個假說,擁有部份自我蛋白質溶解的EGF-TM7,像是CD97,在自然環境同時擁有二個有功能的蛋白質構型 (cleavable and un-cleavable form),而這兩個構型的表現是透過N-醣苷化作用來調控;而決定新生成的胜肽鏈摺疊成可切割的構型(cleavable form)抑或不可切割的構型(un-cleavable)是由於這二個蛋白質構型上胜肽鏈擁有不同位置N-醣苷化所造成的。這些結果對於探討GPS 蛋白溶解的分子及生化特性很重要,同時對於未來研究LNB-TM7的生化、細胞功能以及與疾病之間的關係有很大的幫助。
The LNB-TM7 molecules belong to a subfamily of class B G protein-coupled receptor (GPCR) and are characterized by a novel hybrid structure that contains a long N-terminal extracellular domain connected to a 7TM domain by a mucin-like spacer. Based upon their unique structure, it has been suggested that the LNB-TM7 molecules may play a role in the cellular functions by interacting with other cell surface proteins or extracellular matrix proteins, leading to signal transduction via the 7TM domain. Indeed, the functional importance of the LNB-TM7 proteins has been demonstrated in several human diseases such as Usher syndrome type II and bilateral frontoparietal polymicrogyria (BFPP). The majority of LNB-TM7 receptors are known to undergo a novel post-translational cleavage event at the GPCR proteolytic site (GPS) motif and express on the cell surface as a heterodimeric receptor composed of an extracellular α-subunit and a TM7 β-subunit. Therefore, it is believed that the commonly used GPS cleavage is highly relevant to the functions of the LNB-TM7 receptors. In recent year, the molecular mechanism of the GPS cleavage has been identified and shown to be a self-catalyzed auto-proteolytic reaction. Although the molecular mechanism of the GPS proteolysis has been demonstrated, how this auto-proteolytic reaction is regulated has not been elucidated.
We investigate the regulation of GPS autoproteolysis using EMR2 and CD97 as a model system. These molecules are two highly homologous receptors and have different GPS cleavage efficiencies. A series of chimerical molecules consisting of EMR2 and CD97 protein suggest that the mucin-like stalk region is important in controlling the GPS autoproteolysis. However, treatment of CD97-mFc and EMR2-mFc transfected cell with N-glycosylation inhibitor (tunicamycin) reduced autoproteolysis. This result suggests that N-glycosylation might regulate GPS auto-proteolysis and other N-glycosylation inhibitor treatment support that EGF-TM7 cleavage occurs after the transfer of the oligosaccharide precursor, but does not require its subsequent processing. To investigate the role of N-glycosylation in regulating GPS cleavage efficiency, we establish different N-glycosylation site mutants of CD97 and EMR2 and find GPS cleavage efficiency is influenced by site-specific N-glycosylation. We propose that site-specific N-glycosylation at the mucin-like stalk is involved in receptor protein folding and GPS-autoproteolysis. In this study, we confirmed the intracellular location where PC1 cleavage takes place, and suggests CD97 have two functional conformations (cleaved form and un-cleaved form) in the cell, therefore the oligosaccharide side chains occupy the different N-glycosylation site on the polypeptide decided that CD97-mFc polypeptide folded cleaved conformation or uncleavable conformation.
Chapter 1: Introductions.............................................................................................1
1.1. The adhesion family of GPCRs: LNB-TM7 receptors..................................1
1.2. The identification of the molecular mechanism mediating the proteolytic
cleavage at the GPS motif.....................................................................................4
1.3. The functional role(s) of GPS autoproteolysis in LNB-TM7 receptor
biology....................................................................................................................6
1.4. EGF-TM7 family............................................................................................7
1.5. Protein N-glycosylation..................................................................................8
1.6. Specific Aims................................................................................................11
Chapter 2: Materials and Methods ..........................................................................13
2.1. General Materials ........................................................................................13
2.1.1. General chemicals and solutions .......................................................13
2.1.2. Molecular biology reagents ...............................................................14
2.2. DNA Methods ...............................................................................................15
2.2.1. Polymerase chain reaction (PCR) .....................................................15
2.2.2. Colony PCR .......................................................................................16
2.2.3. High fidelity PCR...............................................................................16
2.2.4. Agarose gel electrophoresis ...............................................................17
2.2.5. Topo ligation ......................................................................................18
2.2.6. Restriction digestion ..........................................................................18
2.2.7. Plasmid DNA precipitation................................................................19
2.2.8. DNA ligation ......................................................................................19
2.2.9. Competent cell preparation ...............................................................19
2.2.10. Transformation of competent bacteria.............................................20
2.2.11. Mini and midi preparation of plasmid DNA ....................................21
2.2.12. Sequencing .......................................................................................21
2.3. Cell Culture ..................................................................................................21
2.3.1. Cell lines ............................................................................................21
2.3.2. Cell subculture ...................................................................................22
2.3.3. Transient transfection of cell lines using calcium phosphate
precipitation.................................................................................................23
2.3.4. Transient transfection of cell lines using LipofectamineTM (Invitrogen)
......................................................................................................................24
2.3.5. N-glycosylation inhibitor treatment ...................................................24
2.4. Protein Methods ...........................................................................................25
2.4.1. Preparation of cell lysates .................................................................25
2.4.2. Protein quantification ........................................................................25
2.4.3. Cell conditioned medium collection...................................................26
2.4.4. SDS-Polyacrylamide gel electrophoresis (PAGE) .............................26
2.4.5. Western blotting .................................................................................26
2.4.6. Purification of mFc-fusion protein by Protein G Affinity
Chromatography ..........................................................................................27
2.4.7. In vitro cleavage reaction ..................................................................28
2.4.8. Quantitative analysis of protein bands ..............................................28
2.5. DNA Expression Constructs ........................................................................28
2.5.1. Generation of site directed mutant constructs (overlapping PCR)....28
2.3.2. Construction of expression vectors ....................................................29
Chapter 3: Results......................................................................................................33
3.1. EMR2 and CD97 are two highly homologous molecule, have different
GPS cleavage efficiencies ...................................................................................33
3.2. CD97 partial proteolysis is not an incomplete autoproteolytic reaction ....34
3.3. The role of the mucin-like region and the GPS motif in the proteolytic
cleavage ...............................................................................................................35
3.4. The GPS autoproteolysis of EGF-TM7.......................................................36
3.5. The role of N-glycosylation EGF-TM7 GPS proteolysis and subcellular
localization of its cleavage ..................................................................................37
3.6. N-glycosylation site mutations on CD97 and EMR2..................................38
3.7. Uncleaved CD97 mutation constructs did not result in incomplete
autoproteolytic reaction ......................................................................................40
Chapter 4: Discussion................................................................................................42
Chapter 5: References ...............................................................................................48
Chapter 6: Figures .....................................................................................................58
Appendix.....................................................................................................................88
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