Cryo-EM structures of the mammalian endo-lysosomal TRPML1 channel elucidate the combined regulation mechanism.
10.1007/s13238-017-0476-5
- Author:
Sensen ZHANG
1
;
Ningning LI
2
;
Wenwen ZENG
3
;
Ning GAO
4
;
Maojun YANG
5
Author Information
1. Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
2. State Key Laboratory of Membrane Biology, Peking-Tsinghua Center for Life Sciences, School of Life Science, Peking University, Beijing, 100871, China.
3. Institute for Immunology and School of Medicine, Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China.
4. State Key Laboratory of Membrane Biology, Peking-Tsinghua Center for Life Sciences, School of Life Science, Peking University, Beijing, 100871, China. gaon@pku.edu.cn.
5. Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China. maojunyang@tsinghua.edu.cn.
- Publication Type:Journal Article
- Keywords:
combined regulation mechanism;
mTRPML1;
mucolipidosis type IV;
structual comparisons
- MeSH:
Animals;
Calcium;
metabolism;
Cryoelectron Microscopy;
Endocytosis;
Endosomes;
metabolism;
Gene Expression;
HEK293 Cells;
Humans;
Hydrogen-Ion Concentration;
Lysosomes;
metabolism;
Mice;
Models, Biological;
Mucolipidoses;
genetics;
metabolism;
pathology;
Nanostructures;
chemistry;
ultrastructure;
Phosphatidylinositols;
metabolism;
Transgenes;
Transient Receptor Potential Channels;
chemistry;
genetics;
metabolism
- From:
Protein & Cell
2017;8(11):834-847
- CountryChina
- Language:English
-
Abstract:
TRPML1 channel is a non-selective group-2 transient receptor potential (TRP) channel with Ca permeability. Located mainly in late endosome and lysosome of all mammalian cell types, TRPML1 is indispensable in the processes of endocytosis, membrane trafficking, and lysosome biogenesis. Mutations of TRPML1 cause a severe lysosomal storage disorder called mucolipidosis type IV (MLIV). In the present study, we determined the cryo-electron microscopy (cryo-EM) structures of Mus musculus TRPML1 (mTRPML1) in lipid nanodiscs and Amphipols. Two distinct states of mTRPML1 in Amphipols are added to the closed state, on which could represent two different confirmations upon activation and regulation. The polycystin-mucolipin domain (PMD) may sense the luminal/extracellular stimuli and undergo a "move upward" motion during endocytosis, thus triggering the overall conformational change in TRPML1. Based on the structural comparisons, we propose TRPML1 is regulated by pH, Ca, and phosphoinositides in a combined manner so as to accommodate the dynamic endocytosis process.
