Protein Science, Vol 7, Issue 2 270-282, Copyright © 1998 by Cold Spring Harbor Laboratory Press

ARTICLE

An interaction-based analysis of calcium-induced conformational changes in Ca(2+) sensor proteins

M. R. NELSON and W. J. CHAZIN
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037

Calcium sensor proteins translate transient increases in intracellular calcium levels into metabolic or mechanical responses, by undergoing dramatic conformational changes upon Ca(2+) binding. A detailed analysis of the calcium binding-induced conformational changes in the representative calcium sensors calmodulin (CaM) and troponin C was performed to obtain insights into the underlying molecular basis for their response to the binding of calcium. Distance difference matrices, analysis of interresidue contacts, comparisons of interhelical angles, and inspection of structures using molecular graphics were used to make unbiased comparisons of the various structures. The calcium-induced conformational changes in these proteins are dominated by reorganization of the packing of the four helices within each domain. Comparison of the closed and open conformations confirms that calcium binding causes opening within each of the EF-hands. A secondary analysis of the conformation of the C-terminal domain of CaM (CaM-C) clearly shows that CaM-C occupies a closed conformation in the absence of calcium that is distinct from the semi-open conformation observed in the C-terminal EF-hand domains of myosin light chains. These studies provide insight into the structural basis for these changes and into the differential response to calcium binding of various members of the EF-hand calcium-binding protein family. Factors contributing to the stability of the Ca(2+)-loaded open conformation are discussed, including a new hypothesis that critical hydrophobic interactions stabilize the open conformation in Ca(2+) sensors, but are absent in ``non-sensor'' proteins that remain closed upon Ca(2+) binding. A role for methionine residues in stabilizing the open conformation is also proposed.
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