4.8 Article

Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels

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NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-04586-x

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资金

  1. Natural Sciences and Engineering Research Council of Canada (NSERC)
  2. National Natural Science Foundation of China [81570648, 81602448]
  3. Deutsche Forschungsgemeinschaft (DFG) [Sonderforschungsbereich 894, Transregio 152]
  4. National Institutes of Health (NIH) [DK102092, R01 DK110575-01]
  5. Alberta Innovates-Doctoral Graduate Student Scholarship
  6. NSERC IRTG Studentship
  7. International Research Training Group 1830 Student Scholarship (DFG)

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PKD2 and PKD1 genes are mutated in human autosomal dominant polycystic kidney disease. PKD2 can form either a homomeric cation channel or a heteromeric complex with the PKD1 receptor, presumed to respond to ligand(s) and/or mechanical stimuli. Here, we identify a two-residue hydrophobic gate in PKD2L1, and a single-residue hydrophobic gate in PKD2. We find that a PKD2 gain-of-function gate mutant effectively rescues PKD2 knockdown-induced phenotypes in embryonic zebrafish. The structure of a PKD2 activating mutant F604P by cryo-electron microscopy reveals a p-to a-helix transition within the pore-lining helix S6 that leads to repositioning of the gate residue and channel activation. Overall the results identify hydrophobic gates and a gating mechanism of PKD2 and PKD2L1.

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