The long β2,3-sheets encoded by redundant sequences play an integral role in the channel function of P2X7 receptors.
The long β2,3-sheets encoded by redundant sequences play an integral role in the channel function of P2X7 receptors.
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由冗余序列编码的长β2,3-片在P2X7受体的通道功能中发挥着不可或缺的作用
DOI：
10.1016/j.jbc.2022.102002
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发表时间：
2022-06
影响因子：
4.8
通讯作者：
Wang, Jin
中科院分区：
文献类型：
--
作者：
Ma, Xue-Fei;Wang, Ting-Ting;Wang, Wen-Hui;Guan, Li;Guo, Chang-Run;Li, Xing-Hua;Lei, Yun-Tao;Fan, Ying-Zhe;Yang, Xiao-Na;Hattori, Motoyuki;Nureki, Osamu;Zhu, Michael X.;Yu, Ye;Tian, Yun;Wang, Jin
P2X受体是一类非选择性阳离子通道，广泛分布于免疫和神经系统，其功能障碍是肿瘤、炎症、白血病和免疫性疾病的重要原因。P2X7是P2X受体家族中一个独特的成员，具有许多不同于其他亚型的特性，在初级序列、N-和C-末端的结构以及通道功能方面都不同。在这里，我们认为由冗余序列编码的加长的β2-和β3-Sheet及其连接子(环β2，3)在P2X7受体的激活中起着不可或缺的作用。我们发现，这个较长的结构元件的缺失会导致P2X7功能的丧失。此外，通过结合突变、嵌合体构建、表面表达和蛋白质稳定性分析，我们发现较长的β2，3-环的缺失影响了P2X7的表面表达，但更重要的是，这个环影响了P2X7的通道门控。我们认为，较长的β2，3-折叠可能对头部结构域上的环和由E171及其周围区域形成的结构元件产生负调控作用。了解P2X7受体的独特结构在门控过程中的作用将有助于开发针对这一亚型的选择性药物。
P2X receptors are a class of nonselective cation channels widely distributed in the immune and nervous systems, and their dysfunction is a significant cause of tumors, inflammation, leukemia, and immune diseases. P2X7 is a unique member of the P2X receptor family with many properties that differ from other subtypes in terms of primary sequence, the architecture of N- and C-terminals, and channel function. Here, we suggest that the observed lengthened β2- and β3-sheets and their linker (loop β2,3), encoded by redundant sequences, play an indispensable role in the activation of the P2X7 receptor. We show that deletion of this longer structural element leads to the loss of P2X7 function. Furthermore, by combining mutagenesis, chimera construction, surface expression, and protein stability analysis, we found that the deletion of the longer β2,3-loop affects P2X7 surface expression but, more importantly, that this loop affects channel gating of P2X7. We propose that the longer β2,3-sheets may have a negative regulatory effect on a loop on the head domain and on the structural element formed by E171 and its surrounding regions. Understanding the role of the unique structure of the P2X7 receptor in the gating process will aid in the development of selective drugs targeting this subtype.
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DOI：
10.1016/j.jbc.2021.100655
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Chen PF;Ma XF;Sun LF;Tian Y;Fan YZ;Li P;Xiao Z;Zhu MX;Guo CR;Li C;Yu Y;Wang J
通讯作者：
Wang J
影响因子：
64.8
作者：
BRAKE, AJ;WAGENBACH, MJ;JULIUS, D
通讯作者：
JULIUS, D
影响因子：
5.6
作者：
Bhattacharya A
通讯作者：
Bhattacharya A
影响因子：
7.3
作者：
Amadio S;Parisi C;Piras E;Fabbrizio P;Apolloni S;Montilli C;Luchetti S;Ruggieri S;Gasperini C;Laghi-Pasini F;Battistini L;Volonté C
通讯作者：
Volonté C
DOI：
10.1016/bs.pmch.2019.11.002
发表时间：
2020-01-01
期刊：
PROGRESS IN MEDICINAL CHEMISTRY, VOL. 59
影响因子：
--
作者：
Gelin, Christine F.;Bhattacharya, Anindya;Letavic, Michael A.
通讯作者：
Letavic, Michael A.