Abstract
Transient receptor potential mucolipin 1 (TRPML1) is a Ca2+-permeable, nonselective cation channel ubiquitously expressed in the endolysosomes of mammalian cells and its loss-of-function mutations are the direct cause of type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease. TRPML1 is a ligand-gated channel that can be activated by phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] as well as some synthetic small-molecule agonists. Recently, rapamycin has also been shown to directly bind and activate TRPML1. Interestingly, both PI(3,5)P2 and rapamycin have low efficacy in channel activation individually but together they work cooperatively and activate the channel with high potency. To reveal the structural basis underlying the synergistic activation of TRPML1 by PI(3,5)P2 and rapamycin, we determined the high-resolution cryoelectron microscopy (cryo-EM) structures of the mouse TRPML1 channel in various states, including apo closed, PI(3,5)P2-bound closed, and PI(3,5)P2/temsirolimus (a rapamycin analog)-bound open states. These structures, combined with electrophysiology, elucidate the molecular details of ligand binding and provide structural insight into how the TRPML1 channel integrates two distantly bound ligand stimuli and facilitates channel opening.
Highlights
Transient receptor potential mucolipin 1 (TRPML1) is a Ca2+-permeable, nonselective cation channel ubiquitously expressed in the endolysosomes of mammalian cells and its loss-of-function mutations are the direct cause of type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease
Loss-of-function mutations in human transient receptor potential mucolipin 1 (TRPML1) are the direct cause of the lysosomal storage disorder mucolipidosis type IV, a neurodegenerative disease characterized by abnormal neurodevelopment, retinal degeneration, and iron-deficiency anemia [17,18,19,20]
It is possible that some other cellular factors participate in the activation or Rapamycin is a natural macrocyclic lactone initially isolated from Streptomyces hygroscopicus [1]
Summary
Structural mechanism of allosteric activation of TRPML1 by PI[3,5]P2 and rapamycin. Ninghai Gana,b,c, Yan Hana,b,c , Weizhong Zenga,b,c, Yan Wanga,b,c, Jing Xuea,b,c, and Youxing Jianga,b,c,1. To reveal the structural basis underlying the synergistic activation of TRPML1 by PI[3,5]P2 and rapamycin, we determined the high-resolution cryoelectron microscopy (cryoEM) structures of the mouse TRPML1 channel in various states, including apo closed, PI[3,5]P2-bound closed, and PI[3,5]P2/temsirolimus (a rapamycin analog)-bound open states. Rapamycin can activate transient receptor potential mucolipin 1 (TRPML1), a phosphatidylinositol 3,5-bisphosphate [PI[3,5]P2]–gated lysosomal cation channel whose loss-of-function mutations directly cause mucolipidosis type IV disease. We determined the high-resolution cryoelectron microscopy structures of TRPML1 in various ligand-bound states, including the open TRPML1 in complex with PI[3,5]P2 and a rapamycin analog at 2.1 Å These structures reveal how rapamycin and PI[3,5]P2 bind at two distinct sites and allosterically activate the channel. All determined at high resolution, these structures provide clear visualization of the molecular details of protein–ligand interactions in TRPML1 and reveal the structural basis underlying the synergistic gating of TRPML1 by rapamycin and PI[3,5]P2
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