Human TRPML1 channel structures in open and closed conformations

Philip Schmiege, Michael Fine, Günter Blobel () and Xiaochun Li ()
Additional contact information
Philip Schmiege: Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University
Michael Fine: University of Texas Southwestern Medical Center
Günter Blobel: Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University
Xiaochun Li: Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University

Nature, 2017, vol. 550, issue 7676, 366-370

Abstract: Abstract Transient receptor potential mucolipin 1 (TRPML1) is a Ca2+-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.

Date: 2017
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/nature24036 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:550:y:2017:i:7676:d:10.1038_nature24036

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature24036

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().