Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation
Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable cation channel required for immune cell activation, insulin secretion, and body heat control. TRPM2 is activated by cytosolic Ca2+, phosphatidyl-inositol-4,5-bisphosphate and ADP ribose. Here, we present the ~3 Å resolution electr...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/36409 |
| _version_ | 1811201260103139328 |
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| author | Zhe Zhang Balázs Tóth Andras Szollosi Jue Chen László Csanády |
| author_facet | Zhe Zhang Balázs Tóth Andras Szollosi Jue Chen László Csanády |
| author_sort | Zhe Zhang |
| collection | DOAJ |
| description | Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable cation channel required for immune cell activation, insulin secretion, and body heat control. TRPM2 is activated by cytosolic Ca2+, phosphatidyl-inositol-4,5-bisphosphate and ADP ribose. Here, we present the ~3 Å resolution electron cryo-microscopic structure of TRPM2 from Nematostella vectensis, 63% similar in sequence to human TRPM2, in the Ca2+-bound closed state. Compared to other TRPM channels, TRPM2 exhibits unique structural features that correlate with its function. The pore is larger and more negatively charged, consistent with its high Ca2+ selectivity and larger conductance. The intracellular Ca2+ binding sites are connected to the pore and cytosol, explaining the unusual dependence of TRPM2 activity on intra- and extracellular Ca2+. In addition, the absence of a post-filter motif is likely the cause of the rapid inactivation of human TRPM2. Together, our cryo-EM and electrophysiology studies provide a molecular understanding of the unique gating mechanism of TRPM2. |
| first_indexed | 2024-04-12T02:19:08Z |
| format | Article |
| id | doaj.art-9472dc29166a450e8c0dac3086b1b664 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:19:08Z |
| publishDate | 2018-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-9472dc29166a450e8c0dac3086b1b6642022-12-22T03:52:10ZengeLife Sciences Publications LtdeLife2050-084X2018-05-01710.7554/eLife.36409Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulationZhe Zhang0Balázs Tóth1Andras Szollosi2https://orcid.org/0000-0002-5570-4609Jue Chen3https://orcid.org/0000-0003-2075-4283László Csanády4https://orcid.org/0000-0002-6547-5889Laboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, United States; Howard Hughes Medical Institute, Chevy Chase, United StatesDepartment of Medical Biochemistry, Semmelweis University, Budapest, Hungary; MTA-SE Ion Channel Research Group, Semmelweis University, Budapest, HungaryDepartment of Medical Biochemistry, Semmelweis University, Budapest, Hungary; MTA-SE Ion Channel Research Group, Semmelweis University, Budapest, HungaryLaboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, United States; Howard Hughes Medical Institute, Chevy Chase, United StatesDepartment of Medical Biochemistry, Semmelweis University, Budapest, Hungary; MTA-SE Ion Channel Research Group, Semmelweis University, Budapest, HungaryTransient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable cation channel required for immune cell activation, insulin secretion, and body heat control. TRPM2 is activated by cytosolic Ca2+, phosphatidyl-inositol-4,5-bisphosphate and ADP ribose. Here, we present the ~3 Å resolution electron cryo-microscopic structure of TRPM2 from Nematostella vectensis, 63% similar in sequence to human TRPM2, in the Ca2+-bound closed state. Compared to other TRPM channels, TRPM2 exhibits unique structural features that correlate with its function. The pore is larger and more negatively charged, consistent with its high Ca2+ selectivity and larger conductance. The intracellular Ca2+ binding sites are connected to the pore and cytosol, explaining the unusual dependence of TRPM2 activity on intra- and extracellular Ca2+. In addition, the absence of a post-filter motif is likely the cause of the rapid inactivation of human TRPM2. Together, our cryo-EM and electrophysiology studies provide a molecular understanding of the unique gating mechanism of TRPM2.https://elifesciences.org/articles/36409cryo-EMpatch-clampion channelstructure-functiongatingpermeation |
| spellingShingle | Zhe Zhang Balázs Tóth Andras Szollosi Jue Chen László Csanády Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation eLife cryo-EM patch-clamp ion channel structure-function gating permeation |
| title | Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation |
| title_full | Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation |
| title_fullStr | Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation |
| title_full_unstemmed | Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation |
| title_short | Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation |
| title_sort | structure of a trpm2 channel in complex with ca2 explains unique gating regulation |
| topic | cryo-EM patch-clamp ion channel structure-function gating permeation |
| url | https://elifesciences.org/articles/36409 |
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