Structural basis for Ca2+ activation of the heteromeric PKD1L3/PKD2L1 channel

Qiang Su (), Mengying Chen, Yan Wang, Bin Li, Dan Jing, Xiechao Zhan, Yong Yu () and Yigong Shi ()
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Qiang Su: Westlake University
Mengying Chen: Tsinghua University
Yan Wang: St. John’s University
Bin Li: St. John’s University
Dan Jing: Westlake University
Xiechao Zhan: Westlake University
Yong Yu: St. John’s University
Yigong Shi: Westlake University

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract The heteromeric complex between PKD1L3, a member of the polycystic kidney disease (PKD) protein family, and PKD2L1, also known as TRPP2 or TRPP3, has been a prototype for mechanistic characterization of heterotetrametric TRP-like channels. Here we show that a truncated PKD1L3/PKD2L1 complex with the C-terminal TRP-fold fragment of PKD1L3 retains both Ca2+ and acid-induced channel activities. Cryo-EM structures of this core heterocomplex with or without supplemented Ca2+ were determined at resolutions of 3.1 Å and 3.4 Å, respectively. The heterotetramer, with a pseudo-symmetric TRP architecture of 1:3 stoichiometry, has an asymmetric selectivity filter (SF) guarded by Lys2069 from PKD1L3 and Asp523 from the three PKD2L1 subunits. Ca2+-entrance to the SF vestibule is accompanied by a swing motion of Lys2069 on PKD1L3. The S6 of PKD1L3 is pushed inward by the S4-S5 linker of the nearby PKD2L1 (PKD2L1-III), resulting in an elongated intracellular gate which seals the pore domain. Comparison of the apo and Ca2+-loaded complexes unveils an unprecedented Ca2+ binding site in the extracellular cleft of the voltage-sensing domain (VSD) of PKD2L1-III, but not the other three VSDs. Structure-guided mutagenic studies support this unconventional site to be responsible for Ca2+-induced channel activation through an allosteric mechanism.

Date: 2021
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DOI: 10.1038/s41467-021-25216-z

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