7d7f
Structure of PKD1L3-CTD/PKD2L1 in calcium-bound state
Structural highlights
FunctionPK2L1_MOUSE Pore-forming subunit of a ciliary calcium channel that controls calcium concentration within primary cilia without affecting cytoplasmic calcium concentration. Forms a heterodimer with PKD1L1 in primary cilia and forms a calcium-permeant ciliary channel that regulates sonic hedgehog/SHH signaling and GLI2 transcription. May act as a sour taste receptor by forming a calcium channel with PKD1L3 in gustatory cells; however, its contribution to sour taste perception is unclear in vivo and may be indirect. May play a role in the perception of carbonation taste.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedThe 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 Ca(2+) and acid-induced channel activities. Cryo-EM structures of this core heterocomplex with or without supplemented Ca(2+) were determined at resolutions of 3.1 A and 3.4 A, 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. Ca(2+)-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 Ca(2+)-loaded complexes unveils an unprecedented Ca(2+) 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 Ca(2+)-induced channel activation through an allosteric mechanism. Structural basis for Ca(2+) activation of the heteromeric PKD1L3/PKD2L1 channel.,Su Q, Chen M, Wang Y, Li B, Jing D, Zhan X, Yu Y, Shi Y Nat Commun. 2021 Aug 11;12(1):4871. doi: 10.1038/s41467-021-25216-z. PMID:34381056[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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