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- W2009043276 abstract "Autosomal dominant polycystic kidney disease (ADPKD) is the most common, monogenic cause of kidney failure in humans. Most cases of ADPKD are linked with mutations in polycystin-1 (PC1) and polycystin-2 (PC2). PC2 is a calcium (Ca2+) permeable channel in the TRP channel family. Deletion of the C-terminus of PC2 alters Ca2+-signaling; the most common pathogenic mutations in PC2 are premature truncations. We previously showed that this tail consists of three functional regions: an unpaired EF-hand domain (PC2-EF), an oligomeric coiled coil domain, and a linker connecting them. We hypothesize that the EF-hand serves as a Ca2+-sensor/switch, and show that PC2 undergoes Ca2+-induced conformational changes by NMR, CD, and SAXS. We have solved the NMR structure of Ca2+-bound PC2-EF and have identified residues with chemical shift changes upon Ca2+-titration. PC2-EF contains a novel unpaired EF-hand fold which may have evolved from a canonical paired EF-hand found in invertebrate PC2 homologs. Human PC2-EF contains a divergent helix-loop-helix in place of a second EF-hand. Temperature dependent steady state NOE experiments and NMR linewidth measurements indicate increased molecular motion in the EF-hand consistent with a proposed role for PC2-EF as a Ca2+-sensitive regulator. Structure-based sequence conservation analysis reveals a conserved hydrophobic pocket in this region, where PC2-EF may mediate Ca2+-dependent protein interactions. Using results of our structural studies we have examined the role of the EF-hand and coiled coil on PC2 channel function in single-channel lipid bilayers. Our results suggest that the coiled coil regulates PC2 by serving as an homo-oligomerization motif, whereas the EF-hand modulates the Ca2+-dependence of PC2 channel activity. Based on our results we propose a mechanism of regulation of the Ca2+-dependence of PC2 channel activity by PC2-EF." @default.
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- W2009043276 date "2010-01-01" @default.
- W2009043276 modified "2023-09-29" @default.
- W2009043276 title "Polycystin-2 Contains an Unpaired EF-hand Motif which May Serve as a Ca2+-Sensitive Regulator of Polycystin-2 Channel Activity" @default.
- W2009043276 doi "https://doi.org/10.1016/j.bpj.2009.12.2890" @default.
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