| First Author | Su Q | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 4871 |
| PubMed ID | 34381056 | Mgi Jnum | J:355637 |
| Mgi Id | MGI:6753971 | Doi | 10.1038/s41467-021-25216-z |
| Citation | Su Q, et al. (2021) Structural basis for Ca(2+) activation of the heteromeric PKD1L3/PKD2L1 channel. Nat Commun 12(1):4871 |
| abstractText | 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 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. |
