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Calpain silencing by a reversible intrinsic mechanism


Uncontrolled activation of calpain can lead to necrotic cell death and irreversible tissue damage. We have discovered an intrinsic mechanism whereby the autolysis-generated protease core fragment of calpain is inactivated through the inherent instability of a key α-helix. This auto-inactivation state was captured by the 1.9 Å Ca2+-bound structure of the protease core from m-calpain, and sequence alignments suggest that it applies to about half of the calpain isoforms. Intact calpain large subunits are also subject to this inhibition, which can be prevented through assembly of the heterodimers. Other isoforms or their released cores are not silenced by this mechanism and might contribute to calpain patho-physiologies.

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Figure 1: Properties of m-calpain protease core and hybrid calpain.
Figure 2: Structural comparison of the calcium-bound μ- and m-minicalpains.
Figure 3: Structural changes at the active site of mI-II.
Figure 4: Hydrophobic core collapses in mI-II but not in μI-II.
Figure 5: DIII confers structural support to the labile protease core from m-calpain.
Figure 6: Heterodimer reconstitution.

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This work was funded by the Government of Canada's Network of Centres of Excellence program supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council through PENCE (the Protein Engineering Network of Centres of Excellence), and the Heart and Stroke Foundation of Ontario. P.L.D. was supported by a Killam Research Fellowship, and T.M. by an Ontario Graduate Scholarship. Z.J. is a Canada Research Chair in Structural Biology.

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Correspondence to Peter L. Davies.

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Moldoveanu, T., Hosfield, C., Lim, D. et al. Calpain silencing by a reversible intrinsic mechanism. Nat Struct Mol Biol 10, 371–378 (2003).

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