Human TRPML1 channel structures in open and closed conformations

• Published in: Nature (London) Vol. 550; no. 7676; pp. 366 - 370
• Main Authors: Schmiege, Philip, Fine, Michael, Blobel, Günter, Li, Xiaochun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19-10-2017; Nature Publishing Group
• Subjects: 101/28; 631/443/810; 631/535/1258/1259; 9/74; Amino acids; Apoproteins - chemistry; Apoproteins - ultrastructure; Autophagy; Binding Sites; Calcium homeostasis; Calcium signalling; Capsaicin receptors; Cell membranes; Cryoelectron Microscopy; Fourier transforms; Helices; Homeostasis; Humanities and Social Sciences; Humans; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Ion channels; Ligands; Lipids; Lysosomes; Microscopy; Models, Molecular; Mucolipidoses - metabolism; Mucolipidosis; Mucolipidosis type IV; multidisciplinary; Mutation; Pathogenesis; pH effects; Physiological aspects; Protein Conformation; Regulatory mechanisms (biology); Science; Signal transduction; Structure; Transient Receptor Potential Channels - agonists; Transient Receptor Potential Channels - chemistry; Transient Receptor Potential Channels - ultrastructure; Transient receptor potential proteins
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature24036

Transient receptor potential mucolipin 1 (TRPML1) is a Ca
2+
-releasing cation channel that mediates the calcium signalling and homeostasis of lysosomes. Mutations in TRPML1 lead to mucolipidosis type IV, a severe lysosomal storage disorder. Here we report two electron cryo-microscopy structures of full-length human TRPML1: a 3.72-Å apo structure at pH 7.0 in the closed state, and a 3.49-Å agonist-bound structure at pH 6.0 in an open state. Several aromatic and hydrophobic residues in pore helix 1, helices S5 and S6, and helix S6 of a neighbouring subunit, form a hydrophobic cavity to house the agonist, suggesting a distinct agonist-binding site from that found in TRPV1, a TRP channel from a different subfamily. The opening of TRPML1 is associated with distinct dilations of its lower gate together with a slight structural movement of pore helix 1. Our work reveals the regulatory mechanism of TRPML channels, facilitates better understanding of TRP channel activation, and provides insights into the molecular basis of mucolipidosis type IV pathogenesis.
Two structures of human transient receptor potential mucolipin 1 (TRPML1), in the closed and agonist-bound open states, have been resolved by electron cryo-microscopy.
Closing in on ion channels
Numerous ion channels sit in the membranes of intracellular organelles and are responsible for maintaining concentration gradients and ionic signalling. The transient receptor potential mucolipin (TRPML) channels are Ca(
II
)-releasing channels that are crucial to endolysosomal function. While TRPML channels regulate physiological processes including membrane trafficking and exocytosis, mutations of TRPML1 cause the lysosomal storage disorder mucolipidosis type IV. Three papers in this issue of
Nature
report the structure of TRPML channels by cryo-electron microscopy. Seok-Yong Lee and colleagues report the structure of TRPML3, while studies from teams led by Xiaochun Li and Youxing Jiang present the structure of TRPML1. Together, these studies reveal the open and closed states of the TRPML family, indicating the regulatory mechanisms of these channels. As with most TRP channels, TRPML can be gated by specific lipids, and these studies provide insights into substrate binding and channel activation.