Abstract
Calmodulin (CaM) is a highly conserved 17 kDa eukaryotic protein that
can bind specifically to over 100 protein targets in response to
a Ca$^2+$ signal. Ca$^2+$-CaM requires a considerable degree
of structural plasticity to accomplish this physiological role; however,
the nature and extent of this plasticity remain poorly characterized.
Here, we present the 1.0 A crystal structure of Paramecium tetraurelia
Ca$^2+$-CaM, including 36 discretely disordered residues and
a fifth Ca$^2+$ that mediates a crystal contact. The 36 discretely
disordered residues are located primarily in the central helix and
the two hydrophobic binding pockets, and reveal correlated side-chain
disorder that may assist target-specific deformation of the binding
pockets. Evidence of domain displacements and discrete backbone disorder
is provided by translation-libration-screw (TLS) analysis and multiconformer
models of protein disorder, respectively. In total, the evidence
for disorder at every accessible length-scale in Ca$^2+$-CaM
suggests that the protein occupies a large number of hierarchically
arranged conformational substates in the crystalline environment
and may sample a quasi-continuous spectrum of conformations in solution.
Therefore, we propose that the functionally distinct forms of CaM
are less structurally distinct than previously believed, and that
the different activities of CaM in response to Ca$^2+$ may result
primarily from Ca$^2+$-mediated alterations in the dynamics of
the protein.
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