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

Zheng, Wang; Yang, Xiaoyong; Hu, Ruikun; Cai, Ruiqi; Hofmann, Laura; Wang, Zhifei; Hu, Qiaolin; Liu, Xiong; Bulkley, David; Yu, Yong; Tang, Jingfeng; Flockerzi, Veit; Cao, Ying; Cao, Erhu; Chen, Xing-Zhen

doi:10.1038/s41467-018-04586-x

Cited by 52 publications

(83 citation statements)

References 70 publications

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“…Structural studies by cryo-EM [19][20][21] and recent functional study [43] show that L677 and N681 are either physical or functional lower gate residues (Fig 2A). Structural studies by cryo-EM [19][20][21] and recent functional study [43] show that L677 and N681 are either physical or functional lower gate residues (Fig 2A).…”

Section: Mutation At the Lower Gate Generates A New Gof Pc2 Channelmentioning

confidence: 78%

“…PC1/PC2_AA produced a robust current, while the PC1/PC2_F604P current was much smaller. In the case of PC2_AA, the alanine mutations at L677 and N681 shorten the side chains that form the restriction at the lower gate, directly widening the pore size, and therefore, the channel's overall conformation would remain in a closed state, as the previous study indicated [43]. Mutation F604P abolishes the hydrophobic interaction between S5 and S6, which leads to twisting and rotation of the four PC2 S6 helices to open the lower gate of the homomeric channel [21,43].…”

Section: Discussionmentioning

confidence: 92%

“…Mutation F604P abolishes the hydrophobic interaction between S5 and S6, which leads to twisting and rotation of the four PC2 S6 helices to open the lower gate of the homomeric channel [21,43]. PC1/PC2_AA produced a robust current, while the PC1/PC2_F604P current was much smaller.…”

Section: Discussionmentioning

confidence: 99%

“…This complex shares overall structural similarity to the homotetrameric PC2 channel, with the last two transmembrane domains (S10-S11) of PC1 directly participating in forming the presumed channel pore [42]. PC2_F640P gave rise to robust whole-oocyte currents when expressed in Xenopus laevis oocytes [11,22,43]. This is mainly due to the lack of knowledge on the channel activation mechanism, making functional analysis very challenging.…”

Section: Introductionmentioning

confidence: 99%

“…Despite evidence indicating that PC1 functions as an ion channel subunit in the PC1/PC2 complex, a solid conclusion could not be made since functional evidence is lacking. The cryo-EM structure showed that the F604P mutation leads to twisting and rotation of the distal S6 helix and opening of the lower pore gate [43]. To resolve this, we recently developed gain-of-function (GOF) mutants of the PC2 channel, including the reported F604P mutant [22].…”

Section: Introductionmentioning

confidence: 99%

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The ion channel function of polycystin‐1 in the polycystin‐1/polycystin‐2 complex

Wang

Liu

et al. 2019

EMBO Reports

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Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2 gene, encoding the polycystic kidney disease protein polycystin‐1 and the transient receptor potential channel polycystin‐2 (also known as TRPP2), respectively. Polycystin‐1 and polycystin‐2 form a receptor–ion channel complex located in primary cilia. The function of this complex, especially the role of polycystin‐1, is largely unknown due to the lack of a reliable functional assay. In this study, we dissect the role of polycystin‐1 by directly recording currents mediated by a gain‐of‐function (GOF) polycystin‐1/polycystin‐2 channel. Our data show that this channel has distinct properties from that of the homomeric polycystin‐2 channel. The polycystin‐1 subunit directly contributes to the channel pore, and its eleven transmembrane domains are sufficient for its channel function. We also show that the cleavage of polycystin‐1 at the N‐terminal G protein‐coupled receptor proteolysis site is not required for the activity of the GOF polycystin‐1/polycystin‐2 channel. These results demonstrate the ion channel function of polycystin‐1 in the polycystin‐1/polycystin‐2 complex, enriching our understanding of this channel and its role in ADPKD.

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Section: Mutation At the Lower Gate Generates A New Gof Pc2 Channelmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The ion channel function of polycystin‐1 in the polycystin‐1/polycystin‐2 complex

Wang

Liu

et al. 2019

EMBO Reports

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Transient Receptor Potential Channels and Endothelial Cell Calcium Signaling

Thakore

Earley

2019

Comprehensive Physiology

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The vascular endothelium is a broadly distributed and highly specialized organ. The endothelium has a number of functions including the control of blood vessels diameter through the production and release of potent vasoactive substances or direct electrical communication with underlying smooth muscle cells, regulates the permeability of the vascular barrier, stimulates the formation of new blood vessels, and influences inflammatory and thrombotic processes. Endothelial cells that make up the endothelium express a variety of cell-surface receptors and ion channels on the plasma membrane that are capable of detecting circulating hormones, neurotransmitters, oxygen tension, and shear stress across the vascular wall. Changes in these stimuli activate signaling cascades that initiate an appropriate physiological response. Increases in the global intracellular Ca 2+ concentration and localized Ca 2+ signals that occur within specialized subcellular microdomains are fundamentally important components of many signaling pathways in the endothelium. The transient receptor potential (TRP) channels are a superfamily of cationpermeable ion channels that act as a primary means of increasing cytosolic Ca 2+ in endothelial cells. Consequently, TRP channels are vitally important for the major functions of the endothelium. In this review, we provide an in-depth discussion of Ca 2+-permeable TRP channels in the endothelium and their role in vascular regulation.

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A PKD1L3 splice variant in taste buds is not cleaved at the G protein-coupled receptor proteolytic site

Kashyap

Wang

et al. 2019

Biochemical and Biophysical Research Communications

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Mutations in polycystin proteins PKD1 and TRPP2 lead to autosomal dominant polycystic kidney disease. These two proteins form a receptor-ion channel complex on primary cilia. PKD1 undergoes an autoproteolysis at the N terminal G-protein-coupled receptor proteolytic site (GPS), which is essential for the function of PKD1. Whether GPS cleavage happens in other PKD proteins and its functional consequence has remained elusive. Here we studied the GPS cleavage of PKD1L3, a protein that associates with TRPP3 in taste cells and may play a role in sour taste. Our results show that PKD1L3 also undergoes GPS cleavage. Mutation at the GPS abolishes the cleavage, and the non-cleavable mutant does not traffic to the plasma membrane when associated with TRPP3. We also found that a splicing variant of PKD1L3, which was originally identified in taste buds, is not cleaved. Amino acids L708 and S709, which are missing in this splicing variant, are crucial for the GPS cleavage of PKD1L3 and the trafficking of the PKD1L3/TRPP3 complex. Our results gain insight into the molecular mechanism of the GPS cleavage of PKD1L3. The presence of the non-cleavable variant suggests the potential in vivo function of uncleaved PKD proteins.

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

Cited by 52 publications

References 70 publications

The ion channel function of polycystin‐1 in the polycystin‐1/polycystin‐2 complex

The ion channel function of polycystin‐1 in the polycystin‐1/polycystin‐2 complex

Transient Receptor Potential Channels and Endothelial Cell Calcium Signaling

A PKD1L3 splice variant in taste buds is not cleaved at the G protein-coupled receptor proteolytic site

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