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Figure 6.
Figure 6. Regulation of Heterodimeric Calpain by Ca^2+A
generic model for Ca^2+ bound calpain was constructed by
substituting the Ca^2+ bound structure of DI-II into the human m
calpain heterodimer (Strobl et al., 2000) while overlapping DIV
and VI with the Ca^2+ bound DVI heterodimer structure (Blanchard
et al., 1997). DII was positioned to optimize DIII interactions.
The anchor peptide (red helix) was placed in the Ca^2+-free
conformation where it interacts with DVI (gray). Two consecutive
yet cooperative levels of Ca^2+ regulation are proposed, both
acting on a different segment of the circularized structure.
Stage 1 includes anchor release (Nakagawa et al., 2001), shown
by the red dotted arrow. As well, under certain conditions small
subunit dissociation (Pal et al., 2001) and the potential
binding of Ca^2+ to DIII (Hosfield et al. 2001 and Tompa et al.
2001) may help free the protease region from constraints. Stage
2 is active site assembly (black dotted arrows) as seen in
μI-II. It follows the onset of stage 1 but may also influence
it if the tendency to realign the active site pulls against the
restraint. Ca^2+ ions are colored gold (seen in X-ray
structures) or red (postulated or confirmed by mutagenesis; Dutt
et al., 2000). Transparent spheres in DIV and VI are Ca^2+ at
EF-4 sites that are likely filled only at high CaCl[2] (>20 mM)
concentrations. Calpain association with membranes (double gray
lines) may also contribute to activation (as reviewed in
Nakagawa et al., 2001).
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