Phosphorylation of human calsequestrin: Implications for calcium regulation

Emiliano J. Sanchez, Gerhard R. Munske, Angela Criswell, Hendrik Milting, A. Keith Dunker, Chulhee Kang

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Both cardiac and skeletal calsequestrin (CASQ2 and CASQ1) serve as a major Ca2+ storage/buffer protein in the sarcoplasmic reticulum (SR) by sequestering and releasing large numbers of Ca2+ ions during each muscular contraction and relaxation cycle. CASQ isolated from various species often exists in a phosphorylated form, but phosphorylation's role is not yet understood. Here, the authors identified two phosphorylation sites, Ser 385 and Ser393, for the first time, in human CASQ2 (hCASQ2) by mass-spectroscopy and evaluated the consequences of such phosphorylation. Substitution of these two serines with phosphoserine-mimicking aspartic-acid residues results in a significant increase in helical content, solubility and Ca2+-binding capacity above 6 mM [Ca2+]. However, neither substitution of Ser385 nor Ser393 alone produce any significant changes. Based on the crystal structures of hCASQ2, Ca2+ binding capacity data, turbidity, and light scattering profiles, it was propose that phosphorylation at these two positions produces a disorder-to-order or coil-to-helix transition of the C-terminus, which in turn provides a more stable network of polyanions. Therefore, considering all the previous reports and the new data, the observed dynamic in vivo phosphorylation of CASQ could provide the basis not only for effective regulation of Ca 2+ buffering capacity, but also for the junctional SR trafficking mechanism.

Original languageEnglish (US)
Pages (from-to)195-204
Number of pages10
JournalMolecular and Cellular Biochemistry
Volume353
Issue number1-2
DOIs
StatePublished - Jul 2011

Keywords

  • Ca binding protein
  • Calsequestrin
  • Disorder-to-order transition
  • Phosphorylation
  • SR

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Molecular Biology
  • Cell Biology

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