title: 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 Ca(2+) ions. However, the nature of Ca(2+)-binding sites has not yet been fully characterized. In this study, we employed in silico approaches to identify the Ca(2+) binding sites and to understand the molecular basis of CASQ1-Ca(2+) 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: ) 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 Ca(2+) concentrations ([Ca(2+)]). Our results show that the Ca(2+)-binding sites on CASQ1 differ both in affinity and geometry. The high affinity Ca(2+)-binding sites share a similar geometry and interestingly, the majority of them were found to be induced by increased [Ca(2+)]. We also found that the system shows maximal Ca(2+)-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 [Ca(2+)]. Further, this study shows that the CAS domain assumes a compact structure with an increase in Ca(2+) binding, which suggests that the CAS domain might function as a Ca(2+)-sensor that may be a novel structural motif to sense metal. We propose the term "Dn-motif" for the CAS domain.
authors: CRS4, Bioengineering group, Science and Technology Park Polaris, Piscina Manna, 09010 Pula, CA, Italy.
authors: Amit
authors: A
authors: Kumar
authors: Harapriya
authors: H
authors: Chakravarty
authors: Naresh C
authors: NC
authors: Bal
authors: Tuniki
authors: T
authors: Balaraju
authors: Nivedita
authors: N
authors: Jena
authors: Gauri
authors: G
authors: Misra
authors: Chandralata
authors: C
authors: Bal
authors: Enrico
authors: E
authors: Pieroni
authors: Muthu
authors: M
authors: Periasamy
authors: Ashoke
authors: A
authors: Sharon
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D002155:Calsequestrin / Q000737:chemistry* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D007698:Kinesis; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055550:Protein Stability
chemical_list: D002155:Calsequestrin; D002118:Calcium
references: J Cell Biol. 1987 Jul;105(1):49-56
references: 3497158
references: Eur J Biochem. 1978 May 16;86(2):511-8
references: 95949
references: Cold Spring Harb Symp Quant Biol. 1987;52:579-85
references: 3454279
references: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references: 8744570
references: J Gen Physiol. 2012 Aug;140(2):87-92
references: 22851673
references: FEBS Lett. 1989 Jan 2;242(2):297-300
references: 2914612
references: Proc Natl Acad Sci U S A. 1987 Mar;84(5):1167-71
references: 3469659
references: J Biol Chem. 1988 Apr 5;263(10):4807-12
references: 2832408
references: Biopolymers. 2000-2001;56(4):257-65
references: 11754339
references: J Biol Chem. 2010 May 28;285(22):17188-96
references: 20353949
references: FEBS Lett. 1992 Mar 9;299(2):175-8
references: 1544490
references: Protein Eng. 1995 Feb;8(2):127-34
references: 7630882
references: J Biol Chem. 2003 May 2;278(18):16176-82
references: 12594204
references: J Comput Chem. 2006 Nov 15;27(14):1765-8
references: 16917862
references: Cell Mol Life Sci. 2013 Aug;70(16):2935-45
references: 23109100
references: Biochem J. 2011 Apr 15;435(2):391-9
references: 21265816
references: J Biol Chem. 2012 Jan 13;287(3):1679-87
references: 22123818
references: Gene. 1991 Dec 30;109(2):275-9
references: 1662658
references: J Muscle Res Cell Motil. 1990 Dec;11(6):522-30
references: 2084148
references: Circ Res. 2011 Apr 1;108(7):871-83
references: 21454795
references: J Comput Chem. 2005 Dec;26(16):1781-802
references: 16222654
references: Protein Sci. 1995 Oct;4(10):2019-31
references: 8535238
references: Cardiovasc Res. 2013 May 1;98(2):169-76
references: 23400762
references: J Mol Biol. 2012 Jan 6;415(1):75-91
references: 22099475
references: Nat Struct Biol. 1998 Jun;5(6):476-83
references: 9628486
references: J Biol Chem. 1984 May 25;259(10):6248-52
references: 6725251
references: J Mol Biol. 2007 Nov 2;373(4):1047-57
references: 17881003
references: J Biol Chem. 2012 Mar 30;287(14):11592-601
references: 22337878
references: Prog Biophys Mol Biol. 2004 May;85(1):33-69
references: 15050380
references: Biochemistry. 1989 Aug 8;28(16):6764-71
references: 2790030
references: J Biol Chem. 1984 Oct 10;259(19):11876-81
references: 6480588
references: J Biol Chem. 2004 Apr 23;279(17):18026-33
references: 14871888
references: Gene. 1998 Sep 14;217(1-2):25-30
references: 9795116
references: Proc Natl Acad Sci U S A. 1985 Jun;82(12):4036-40
references: 3858861
references: J Biol Chem. 1983 Oct 10;258(19):11932-6
references: 6619149
references: Mol Med Rep. 2010 Mar-Apr;3(2):199-204
references: 21472222
references: Proteins. 2005 Dec 1;61(4):704-21
references: 16231289
references: J Biol Chem. 1974 Apr 25;249(8):2357-65
references: 4856651