Allostery in Orai1 binding to calmodulin revealed from conformational thermodynamics |
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Authors: | Lakshmi Maganti Sutapa Dutta |
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Affiliation: | Department of Chemical, Biological and Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Sector III, Block JD, Salt Lake, Kolkata 700106, India |
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Abstract: | Here, we study microscopic mechanism of complex formation between Ca2+-bound calmodulin (holoCaM) and Orai1 that regulates Ca2+-dependent inactivation process in eukaryotic cells. We compute conformational thermodynamic changes in holoCaM with respect to complex of Orai1 bound to C-terminal domain of holoCaM using histograms of dihedral angles of the proteins over trajectories from molecular dynamics simulations. Our analysis shows that the N-terminal domain residues L4, T5, Q41, N42, T44 and E67 of holoCaM get destabilized and disordered due to Orai1 binding to C-terminal domain of calmodulin affect the N-terminal domain residues. Among these residues, polar T44, having maximum destabilization and disorder via backbone fluctuations, shows the largest change in solvent exposure. This suggests that N-terminal domain is allosterically regulated via T44 by the binding of Orai1 to the C-terminal domain. |
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Keywords: | calmodulin-Orai1 complex molecular dynamics conformational thermodynamics allostery |
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