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PDBsum entry 2mhh
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Metal binding protein
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PDB id
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2mhh
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References listed in PDB file
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Key reference
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Title
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The number and location of ef hand motifs dictates the calcium dependence of polycystin-2 function.
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Authors
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I.Y.Kuo,
C.Keeler,
R.Corbin,
A.ĆElić,
E.T.Petri,
M.E.Hodsdon,
B.E.Ehrlich.
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Ref.
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Faseb J, 2014,
28,
2332-2346.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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Polycystin 2 (PC2) is a calcium-dependent calcium channel, and mutations to
human PC2 (hPC2) are associated with polycystic kidney disease. The C-terminal
tail of hPC2 contains 2 EF hand motifs, but only the second binds calcium. Here,
we investigate whether these EF hand motifs serve as a calcium sensor
responsible for the calcium dependence of PC2 function. Using NMR and
bioinformatics, we show that the overall fold is highly conserved, but in
evolutionarily earlier species, both EF hands bind calcium. To test whether the
EF hand motif is truly a calcium sensor controlling PC2 channel function, we
altered the number of calcium binding sites in hPC2. NMR studies confirmed that
modified hPC2 binds an additional calcium ion. Single-channel recordings
demonstrated a leftward shift in the calcium dependence, and imaging studies in
cells showed that calcium transients were enhanced compared with wild-type hPC2.
However, biophysics and functional studies showed that the first EF hand can
only bind calcium and be functionally active if the second (native)
calcium-binding EF hand is intact. These results suggest that the number and
location of calcium-binding sites in the EF hand senses the concentration of
calcium required for PC2 channel activity and cellular function.
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