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Duke University Medical Center

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Nature, Published online 11 October 2017 | doi:10.1038/nature24055 Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3

Marscha Hirschi^1*, Mark A.Herzik Jr^2*, Jinhong Wie³, Yang Suo¹, William F. Borschel¹, Dejian Ren³, Gabriel C. Lander^2,* & Seok-Yong Lee^1,*¹Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina 27710, USA. ²Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA. ³Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

^*Correspondence to: Seok-Yong Lee or Gabriel C. Lander

Abstract

The modulation of ion channel activity by lipids is increasingly recognized as a fundamental component of cellular signalling. The transient receptor potential mucolipin (TRPML) channel family belongs to the TRP superfamily^{1, 2} and is composed of three members: TRPML1-TRPML3. TRPMLs are the major Ca²⁺-permeable channels on late endosomes and lysosomes (LEL). They regulate the release of Ca²⁺ from organelles, which is important for various physiological processes, including organelle trafficking and fusion³. Loss-of-function mutations in the MCOLN1 gene, which encodes TRPML1, cause the neurodegenerative lysosomal storage disorder mucolipidosis type IV, and a gain-of-function mutation (Ala419Pro) in TRPML3 gives rise to the varitint-waddler (Va) mouse phenotype^{4, 5, 6}. Notably, TRPML channels are activated by the low-abundance and LEL-enriched signalling lipid phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P₂), whereas other phosphoinositides such as PtdIns(4,5)P₂, which is enriched in plasma membranes, inhibit TRPMLs^{7, 8}. Conserved basic residues at the N terminus of the channel are important for activation by PtdIns(3,5)P₂ and inhibition by PtdIns(4,5)P₂⁸. However, owing to a lack of structural information, the mechanism by which TRPML channels recognize PtdIns(3,5)P₂ and increase their Ca²⁺ conductance remains unclear. Here we present the cryo-electron microscopy (cryo-EM) structure of a full-length TRPML3 channel from the common marmoset (Callithrix jacchus) at an overall resolution of 2.9Å. Our structure reveals not only the molecular basis of ion conduction but also the unique architecture of TRPMLs, wherein the voltage sensor-like domain is linked to the pore via a cytosolic domain that we term the mucolipin domain. Combined with functional studies, these data suggest that the mucolipin domain is responsible for PtdIns(3,5)P₂ binding and subsequent channel activation, and that it acts as a ‘gating pulley’ for lipid-dependent TRPML gating.

논문정보

형식Research article
게재일2017년 10월 (BRIC 등록일 2017-10-19)
연구진국외 연구진
분야 생명과학 > 생화학

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