ArticleProceedings of the National Academy of Sciences of the United States of America2010
Structure of the EF-hand domain of polycystin-2 suggests a mechanism for Ca2+-dependent regulation of polycystin-2 channel activity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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46 citing papers in PubMed, 74 citations in OpenAlex.
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- Structural Insights and Calcium-Switching Mechanism ofInternational journal of molecular sciences · 2025Article
- A Deep Dive into the N-Terminus of STIM Proteins: Structure-Function Analysis and Evolutionary Significance of the Functional Domains.Biomolecules · 2024Review
- Calcium signaling in polycystic kidney disease- cell death and survival.Cell calcium · 2023Review
- Polycystin Channel Complexes.Annual review of physiology · 2023Review
- Transient Receptor Potential Channels: Important Players in Ocular Pain and Dry Eye Disease.Pharmaceutics · 2022Review
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- Disrupting polycystin-2 EF hand CaJournal of cell science · 2020Article
- Structure and function of polycystin channels in primary cilia.Cellular signalling · 2020Review
- Polycystins as components of large multiprotein complexes of polycystin interactors.Cellular signalling · 2020Review
- Polycystin 2: A calcium channel, channel partner, and regulator of calcium homeostasis in ADPKD.Cellular signalling · 2020Review
- Structure and function of polycystins: insights into polycystic kidney disease.Nature reviews. Nephrology · 2019Review
- TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells.Nature communications · 2019Article
- Heat activation mechanism of TRPV1: New insights from molecular dynamics simulation.Temperature (Austin, Tex.) · 2019Review
- Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels.Nature communications · 2018Article
- CaInternational journal of molecular sciences · 2018Review
- Decrypting the Heat Activation Mechanism of TRPV1 Channel by Molecular Dynamics Simulation.Biophysical journal · 2018Article
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6 authors at 2 institutions in 1 country.
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Abstract
The C-terminal cytoplasmic tail of polycystin-2 (PC2/TRPP2), a Ca(2+)-permeable channel, is frequently mutated or truncated in autosomal dominant polycystic kidney disease. We have previously shown that this tail consists of three functional regions: an EF-hand domain (PC2-EF, 720-797), a flexible linker (798-827), and an oligomeric coiled coil domain (828-895). We found that PC2-EF binds Ca(2+) at a single site and undergoes Ca(2+)-dependent conformational changes, suggesting it is an essential element of Ca(2+)-sensitive regulation of PC2 activity. Here we describe the NMR structure and dynamics of Ca(2+)-bound PC2-EF. Human PC2-EF contains a divergent non-Ca(2+)-binding helix-loop-helix (HLH) motif packed against a canonical Ca(2+)-binding EF-hand motif. This HLH motif may have evolved from a canonical EF-hand found in invertebrate PC2 homologs. Temperature-dependent steady-state NOE experiments and NMR R(1) and R(2) relaxation rates correlate with increased molecular motion in the EF-hand, possibly due to exchange between apo and Ca(2+)-bound states, consistent with a role for PC2-EF as a Ca(2+)-sensitive regulator. Structure-based sequence conservation analysis reveals a conserved hydrophobic surface in the same region, which may mediate Ca(2+)-dependent protein interactions. We propose that Ca(2+)-sensing by PC2-EF is responsible for the cooperative nature of PC2 channel activation and inhibition. Based on our results, we present a mechanism of regulation of the Ca(2+) dependence of PC2 channel activity by PC2-EF.
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