Title : Cryo-EM structures of the mammalian endo-lysosomal
TRPML1 channel elucidate the combined regulation mechanism
Abstract :
- TRPML1 channel is a non-selective group-2 transient receptor potential ( TRP ) channel with Ca2 + 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, Ca2 +, and phosphoinositides in a combined manner so as to accommodate the dynamic endocytosis process