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古生代 TRPM2 通道的酶活性和选择性滤器稳定性在早期脊椎动物中同时丧失。

Enzyme activity and selectivity filter stability of ancient TRPM2 channels were simultaneously lost in early vertebrates.

机构信息

Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.

MTA-SE Lendület Ion Channel Research Group, Semmelweis University, Budapest, Hungary.

出版信息

Elife. 2019 Apr 2;8:e44556. doi: 10.7554/eLife.44556.

DOI:10.7554/eLife.44556
PMID:30938679
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6461439/
Abstract

Transient Receptor Potential Melastatin 2 (TRPM2) is a cation channel important for the immune response, insulin secretion, and body temperature regulation. It is activated by cytosolic ADP ribose (ADPR) and contains a nudix-type motif 9 (NUDT9)-homology (NUDT9-H) domain homologous to ADPR phosphohydrolases (ADPRases). Human TRPM2 (hsTRPM2) is catalytically inactive due to mutations in the conserved Nudix box sequence. Here, we show that TRPM2 Nudix motifs are canonical in all invertebrates but vestigial in vertebrates. Correspondingly, TRPM2 of the cnidarian (nvTRPM2) and the choanoflagellate (srTRPM2) are active ADPRases. Disruption of ADPRase activity fails to affect nvTRPM2 channel currents, reporting a catalytic cycle uncoupled from gating. Furthermore, pore sequence substitutions responsible for inactivation of hsTRPM2 also appeared in vertebrates. Correspondingly, zebrafish () TRPM2 (drTRPM2) and hsTRPM2 channels inactivate, but srTRPM2 and nvTRPM2 currents are stable. Thus, catalysis and pore stability were lost simultaneously in vertebrate TRPM2 channels.

摘要

瞬时受体电位 M 亚家族成员 2（TRPM2）是一种阳离子通道，在免疫反应、胰岛素分泌和体温调节中发挥重要作用。它可被细胞质 ADP 核糖（ADPR）激活，含有与 ADPR 磷酸水解酶（ADPRases）同源的 nudix 基序 9（NUDT9）结构域。由于保守的 Nudix 盒序列发生突变，人类 TRPM2（hsTRPM2）失去了催化活性。本研究表明，TRPM2 的 Nudix 基序在所有无脊椎动物中都是典型的，但在脊椎动物中却已退化。相应地，腔肠动物的 TRPM2（nvTRPM2）和领鞭毛虫的 TRPM2（srTRPM2）是具有活性的 ADPRase。破坏 ADPRase 活性并不能影响 nvTRPM2 通道电流，表明其催化循环与门控过程解耦。此外，导致 hsTRPM2 失活的孔序列取代也出现在脊椎动物中。相应地，斑马鱼（）的 TRPM2（drTRPM2）和 hsTRPM2 通道失活，但 srTRPM2 和 nvTRPM2 电流稳定。因此，在脊椎动物 TRPM2 通道中，催化作用和孔稳定性同时丧失。

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