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標題: | 探討在神經退化性疾病裡分子伴侶如何調控蛋白堆積 To Study the Regulation of Chaperone and Co-chaperone in Neurodegenerative Diseases |
作者: | Yi-Ci Ke 柯怡綺 |
指導教授: | 鄧述諄(Shu-Chun Teng) |
關鍵字: | 分子伴侶,ATM/ATR,神經退化性疾病,蛋白磷酸化,老化,DNAJA3,DNAJB11,ErbB-2, chaperone/co-chaperone,ATM/ATR,neurodegenerative diseases,protein phosphorylation,aging,DNAJA3,DNAJB11,ErbB-2, |
出版年 : | 2019 |
學位: | 碩士 |
摘要: | 蛋白質不正常摺疊與堆積在神經退化性疾病中視為重要的病理特徵,在許多的文獻當中也指出老化為造成神經退化性疾病的重要因素。造成老化原因有很多像是氧化壓力以及DNA 受損等,當細胞面臨這些壓力時會啟動修復路徑,最主要的路徑為ATM與ATR,ATM/ATR會磷酸化下游的蛋白進而傳遞一些訊號。然而根據先前實驗室研究發現到分子伴侶 (chaperone/co-chaperone) 的磷酸化會影響到蛋白的摺疊及堆積,有鑑於此,我們推測在ATM/ATR磷酸化下游蛋白中的分子伴侶會影響神經退化性疾病中的蛋白堆積。因此我們根據先前大規模分析在壓力下ATM/ATR磷酸化的受質中挑出分子伴侶,在這11個可能的分子伴侶中進行初步篩選,發現到DNAJA3與DNAJB11蛋白的磷酸化對於下游受質有所影響。
DNAJA3與DNAJB11皆會使ErbB-2蛋白的量下降,ErbB-2為酪氨酸激酶接受器 (tyrosine kinase receptor),在我們的結果中發現到在DNAJA3 S169D與S169A突變後以及DNAJB11 T188E中,ErbB-2的量明顯下降,因此初步認為DNAJA3與DNAJB11的磷酸化是會去影響下游的受質。 Protein aggregation can be found in a variety of diseases such as Parkinson’s and Alzheimer’s diseases. Many stresses at the molecular and cellular levels have been identified to provoke aging and play an important role in neurodegenerative diseases. Upon these stresses induce DNA damage response, ATM and ATR, two central regulators phosphorylate the downstream substrates to transduce signal. From the previous study, we found that the dephosphorylation of a co-chaperone facilitates protein folding under stresses. We speculate that the phosphorylation of chaperones/co-chaperones by stress/aging-induced ATM/ATR may also control the protein folding in neurodegenerative diseases. From the previous large-scale proteomic analysis of proteins phosphorylated by ATM/ATR in response to DNA damage, we found that 11 chaperones/co-chaperones phosphorylated. In my screening, the phosphorylation of DNAJA3 and DNAJB11 might be crucial for protein aggregations. Both DNAJA3 and DNAJB11 facilitate ErbB-2 degradation. DNAJA3 S169D and S169A, the mimetic phosphorylation and dephosphorylation mutations, reduced ErbB-2 than DNAJA3 mutations. However, DNAJB11 T188E, the mimetic phosphorylation, reduced ErbB-2 to a greater extent than DNAJB11 and DNAJB11 T188A. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74291 |
DOI: | 10.6342/NTU201903275 |
全文授權: | 有償授權 |
顯示於系所單位: | 微生物學科所 |
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