Issue 7, 2013

Identification of calcium binding sites on calsequestrin 1 and their implications for polymerization

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.

Graphical abstract: Identification of calcium binding sites on calsequestrin 1 and their implications for polymerization

Supplementary files

Article information

Article type
Paper
Submitted
19 Dec 2012
Accepted
09 Apr 2013
First published
10 Apr 2013

Mol. BioSyst., 2013,9, 1949-1957

Identification of calcium binding sites on calsequestrin 1 and their implications for polymerization

A. Kumar, H. Chakravarty, N. C. Bal, T. Balaraju, N. Jena, G. Misra, C. Bal, E. Pieroni, M. Periasamy and A. Sharon, Mol. BioSyst., 2013, 9, 1949 DOI: 10.1039/C3MB25588C

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