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TitleCryo-EM structures of the mammalian endo-lysosomal TRPML1 channel elucidate the combined regulation mechanism.
Journal, issue, pagesProtein Cell, Vol. 8, Issue 11, Page 834-847, Year 2017
Publish dateSep 21, 2017
AuthorsSensen Zhang / Ningning Li / Wenwen Zeng / Ning Gao / Maojun Yang /
PubMed AbstractTRPML1 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 ...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.
External linksProtein Cell / PubMed:28936784 / PubMed Central
MethodsEM (single particle)
Resolution5.8 Å
Structure data

EMDB-6823, PDB-5ydz:
structure of endo-lysosomal TRPML1 channel inserting into amphipol: state 1
Method: EM (single particle) / Resolution: 5.8 Å

EMDB-6824, PDB-5ye1:
structure of endo-lysosomal TRPML1 channel inserting into amphipol: state 2
Method: EM (single particle) / Resolution: 5.8 Å

EMDB-6825, PDB-5ye2:
mammalian endo-lysosomal TRPML1 channel inserting into amphipol
Method: EM (single particle) / Resolution: 5.8 Å

EMDB-6826, PDB-5ye5:
structure of endo-lysosomal TRPML1 channel inserting into nanodisc
Method: EM (single particle) / Resolution: 5.8 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / mTRPML1 / mucolipidosis type IV / structual comparisons / combined regulation mechanism

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