Identification of calcium binding sites on calsequestrin 1 and their implications for polymerization
- 10 April 2013
- journal article
- research article
- Published by Royal Society of Chemistry (RSC) in Molecular BioSystems
- Vol. 9 (7), 1949-1957
- https://doi.org/10.1039/c3mb25588c
Abstract
Biophysical studies have shown that each molecule of calsequestrin 1 (CASQ1) can bind about 70–80 Ca2+ ions. However, the nature of Ca2+-binding sites has not yet been fully characterized. In this study, we employed in silico approaches to identify the Ca2+ binding sites and to understand the molecular basis of CASQ1–Ca2+ recognition. We built the protein model by extracting the atomic coordinates for the back-to-back dimeric unit from the recently solved hexameric CASQ1 structure (PDB id: 3UOM) and adding the missing C-terminal residues (aa350–364). Using this model we performed extensive 30 ns molecular dynamics simulations over a wide range of Ca2+ concentrations ([Ca2+]). Our results show that the Ca2+-binding sites on CASQ1 differ both in affinity and geometry. The high affinity Ca2+-binding sites share a similar geometry and interestingly, the majority of them were found to be induced by increased [Ca2+]. We also found that the system shows maximal Ca2+-binding to the CAS (consecutive aspartate stretch at the C-terminus) before the rest of the CASQ1 surface becomes saturated. Simulated data show that the CASQ1 back-to-back stacking is progressively stabilized by the emergence of an increasing number of hydrophobic interactions with increasing [Ca2+]. Further, this study shows that the CAS domain assumes a compact structure with an increase in Ca2+ binding, which suggests that the CAS domain might function as a Ca2+-sensor that may be a novel structural motif to sense metal. We propose the term “Dn-motif” for the CAS domain.Keywords
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