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Structure of the EF-hand domain of polycystin-2 suggests a mechanism for Ca2+-dependent regulation of polycystin-2 channel activity. | LitMetric

AI Article Synopsis

  • Polycystin-2 (PC2) is a calcium-permeable channel whose C-terminal tail is linked to autosomal dominant polycystic kidney disease, often showing mutations or truncations.
  • The study details the NMR structure and dynamics of the calcium-binding EF-hand region of PC2, highlighting its role in calcium regulation and its unique features compared to other similar proteins.
  • Findings indicate that the EF-hand in PC2 not only binds calcium but may also facilitate protein interactions, contributing to a cooperative mechanism for activating or inhibiting the PC2 channel based on calcium levels.

Article 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889120PMC
http://dx.doi.org/10.1073/pnas.0912295107DOI Listing

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