研究生: |
辛杰培 Singh, Jai Prakash |
---|---|
論文名稱: |
T細胞酪胺酸去磷酸酶的異位調控:無結構區域造成之自我活性抑制及整聯蛋白alpha-1碳端所促進之酵素活化 The intrinsic disordered C-terminal tail regulates the catalytic activity of T-cell protein tyrosine phosphatase: from allosteric auto-inhibition to activation by Integrin alpha-1 |
指導教授: |
孟子青
Meng, Tzu-Ching 洪嘉呈 HORNG, JIA-CHERNG |
口試委員: |
梁博煌
Liang, Po-Huang 陳佩燁 Chen, Rita P.-Y. 徐尚德 HSU, SHANG-TE 黃介嶸 Huang, Jie-rong |
學位類別: |
博士 Doctor |
系所名稱: |
理學院 - 化學系 Department of Chemistry |
論文出版年: | 2022 |
畢業學年度: | 110 |
語文別: | 英文 |
論文頁數: | 178 |
中文關鍵詞: | 晶體結構 、蛋白酪氨酸磷酸酶 、磷酸酶活性 、催化活性 、變構調節 、自動調節/自動抑制 、核磁共振波譜 |
外文關鍵詞: | T-Cell Protein Tyrosine Phosphatase, Protein tyrosine phosphatase, TCPTP, PTPN2, Phosphatase activity, Helix α7, ITGA1, Auto-regulation/Autoinhibition, CX-MS |
相關次數: | 點閱:3 下載:0 |
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T細胞的蛋白酪胺酸磷酸水解酶 (TCPTP, PTPN2) 是在人體細胞中普遍表達的一種非受體型蛋白酪胺酸磷酸水解酶,在不同的細胞間室中有多種不同的作用受質。它調控關鍵訊息傳遞路徑,並與各種癌症生成、發炎反應以及其他人類疾病的發生息息相關。因此,了解TCPTP活性調控的分子機制對於開發針對TCPTP的治療方法至關重要,然而以結構基礎來詮釋TCPTP活性調控機制仍然難以捉摸。在本研究中,我們結合生物物理學以及生物化學的研究方法,進行全面性結構分析,闡明TCPTP活性調控的分子機制。
由於TCPTP和PTP1B在PTP家族中是最接近的同源物,可以假設此兩種磷酸水解酶的活性調控是相似的。因此,我們首先透過X 射線晶體學來探討TCPTP的活性調控是否也存在在PTP1B的變構位點。在解析度分別為1.7Å及1.9Å的TCPTP晶體結構中,我們都觀察到C 端的螺旋 α7。螺旋 α7在PTP1B上是具有功能性且被確定為其變構開關,然而過往研究並未解析螺旋 α7在TCPTP中的功能。此論文中,我們首次證明螺旋 α7發生截斷或刪除時,TCPTP的催化效率會下降約四倍。整體來說,我們的結果證明螺旋 α7的變構角色在TCPTP活性調控之功能與PTP1B相似,且強調螺旋 α7和主要的催化區域的協調對於TCPTP的有效催化功能是必要的。
根據晶體結構的觀察分析,我們提出更進一步的問題: 如果TCPTP和PTP1B的活性催化調控相似,那該如何區分兩者之間活性調控的專一性? 此一問題的釐清對開發TCPTP的藥物有其必要,因此我們繼續專注地研究TCPTP非催化的C側尾端的活化調控。先前的研究已提出TCPTP被自身的C端滅活的假設,但如何造成此結果則仍未知。此外,如果TCPTP表現後無活性,那其如何在細胞內被激活?為了回答這些問題,我們使用核磁共振 (NMR)光譜學、小角度 X 射線散射 (SAXS)以及化學交聯與質譜偶合 (CX-MS)為主要的工具來闡示TCPTP的尾端無結構序列做為分子內自動抑制其酵素活性機制的主要工具。然而,這並不是靠靜態作用造成,而是C端尾部在活化位點周圍移動,以動態遮擋TCPTP的基質,就像是汽車的”擋風玻璃雨刷”一般的機制。 再者,TCPTP活化是藉由細胞內的競爭來達成,意即Integrin-alpha1無結構尾端序列取代了TCPTP的活性抑制尾端,導致TCPTP的完全活化。我們的工作不僅定義了調控TCPTP活性獨特的機制,同時揭露了兩個極度相近的PTPs (PTP1B與TCPTP) 利用其尾端無結構序列經由截然不同的機制調控其酵素活性。這種獨特的調控機制可以用以發展針對TCPTP專一的治療方式。
T-Cell Protein Tyrosine Phosphatase (TCPTP, PTPN2) is a non-receptor type protein tyrosine phosphatase that is ubiquitously expressed in human cells and targets a broad variety of substrates across different subcellular compartments. It is a critical component of various key signaling pathways that are directly associated with the formation of cancer, inflammation, and other diseases. Thus, understanding the molecular mechanism of TCPTP activity regulation is essential for the development of TCPTP based therapeutics. In spite of that, the structural basis for the regulation of TCPTP’s activity has remained elusive. In this study by using a combination of biophysical and biochemical methods such as nuclear magnetic resonance (NMR), X-ray crystallography, small-angle X-ray scattering (SAXS), chemical cross-linking coupled with mass spectrometry (CX-MS), and enzymatic activity we have carried out comprehensive structural characterization, elucidating the underlying regulatory mechanism of TCPTP’s catalytic activity.
Since TCPTP and PTP1B are the closest homologs within the PTP family, it has been hypothesized that activity of both the phosphatases is regulated in a similar manner. Thus, through X-ray crystallography, we investigated whether the activity of TCPTP could also be regulated by the same allosteric site that comparably exists in PTP1B. We determined two crystal structures of TCPTP at 1.7 Å and 1.9 Å resolution that includes helix α7 at the TCPTP C-terminus. Helix α7 has been functionally characterized in PTP1B and was identified as its allosteric switch. However, its function in TCPTP has been unknown. Here, we demonstrate that truncation or deletion of helix α7 reduced the catalytic efficiency of TCPTP by ~four-fold. Collectively, our data demonstrated an allosteric role of helix α7 in the regulation of TCPTP’s activity similar to its function in PTP1B, and highlights that the coordination of helix α7 with the core catalytic domain is essential for the efficient catalytic function of TCPTP.
Following the observation from crystal structural analysis, we wondered if the catalytic activity of TCPTP and PTP1B is regulated similarly, then how could we specifically tune the activity of TCPTP, which is critically required for the development of TCPTP-based therapeutics. With this objective in mind, we went ahead to investigate if the non-catalytic C-terminal tail of TCPTP regulates the catalytic activity specifically. Indeed, a previous study has suggested that under basal conditions, TCPTP is inactivated by its own C-terminal tail, but how this inactivation is achieved has been unknown. Furthermore, if it is inactive then how can it be activated inside a cell. To answer these questions, we used nuclear magnetic resonance (NMR) spectroscopy, small-angle X-ray scattering (SAXS), and chemical cross-linking coupled with mass spectrometry (CX-MS) as major tools to show that the C-terminal intrinsically disordered tail of TCPTP functions as an intramolecular autoinhibitory element that controls the TCPTP catalytic activity. However, this is not achieved by completely blocking the active site, but rather the C-terminal tail moves around the active site and dynamically occludes substrates from the TCPTP active site which is akin to a ‘windshield wiper’ in a car. Activation of TCPTP is achieved by cellular competition, i.e., the intrinsically disordered cytosolic tail of Integrin-α1 displaces the TCPTP autoinhibitory tail, allowing for the full activation of TCPTP. Taken together our work not only defines the completely unique mechanism by which TCPTP is regulated but also reveals that the intrinsically disordered tails of two of the most closely related PTPs (PTP1B and TCPTP) autoregulate the catalytic activity of their cognate PTPs via entirely different mechanisms, which can be exploited to develop TCPTP based specific therapeutics.
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