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<p>Transient receptor potential melastatin 1 (TRPM1) is a membrane protein essential for vision in dim light, and mutations in TRPM1 cause complete congenital stationary night blindness. Although TRPM1 shares sequence similarity to other TRPM ion channels such as TRPM3, whether it independently functions as an ion channel remains controversial. This controversy is largely caused by TRPM1’s challenging biochemical behaviors that prevent detailed molecular characterization. In this work, we isolate TRPM1 and determine its structures using cryogenic electron microscopy (cryo-EM). The structures reveal a canonical tetrameric fold in the intracellular domain, consistent with other TRPM family members that are ion channels. Surprisingly, in the transmembrane domain, despite the presence of the conserved voltage sensor-like domain (VSLD) and pore domain (PD) in a domain-swapped fashion, the VSLD and PD are arranged with an opposite handedness compared to other related channels. This inverted transmembrane domain allows the formation of a large pore-like structure that supports the role of TRPM1 as an ion channel. This non-canonical architecture of TRPM1 may also confer unique permeation and pharmacological properties.</p>

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Cryo-EM structure of TRPM1 reveals a non-canonical architecture with an inverted transmembrane domain

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月19日

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  • Michael Fabrizio,
  • Mackenzie Brewer,
  • Nebojša Bogdanović,
  • Chen Zhao

摘要

Transient receptor potential melastatin 1 (TRPM1) is a membrane protein essential for vision in dim light, and mutations in TRPM1 cause complete congenital stationary night blindness. Although TRPM1 shares sequence similarity to other TRPM ion channels such as TRPM3, whether it independently functions as an ion channel remains controversial. This controversy is largely caused by TRPM1’s challenging biochemical behaviors that prevent detailed molecular characterization. In this work, we isolate TRPM1 and determine its structures using cryogenic electron microscopy (cryo-EM). The structures reveal a canonical tetrameric fold in the intracellular domain, consistent with other TRPM family members that are ion channels. Surprisingly, in the transmembrane domain, despite the presence of the conserved voltage sensor-like domain (VSLD) and pore domain (PD) in a domain-swapped fashion, the VSLD and PD are arranged with an opposite handedness compared to other related channels. This inverted transmembrane domain allows the formation of a large pore-like structure that supports the role of TRPM1 as an ion channel. This non-canonical architecture of TRPM1 may also confer unique permeation and pharmacological properties.