Polymerization of calsequestrin: Implications for Ca2+ regulation

Ha Jeung Park, Si Wu, A. Keith Dunker, Chul Hee Kang

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

Two distinct dimerization contacts in calsequestrin crystals suggested a mechanism for Ca2+ regulation resulting from the occurrence of coupled Ca2+ binding and protein polymerization. Ca2+-induced formation of one contact was proposed to lead to dimerization followed by Ca2+-induced formation of the second contact to bring about polymerization (1). To test this mechanism, we compared canine cardiac calsequestrin and four truncation mutants with regard to their folding properties, structures, and Ca2+-induced polymerization. The wild-type calsequestrin and truncation mutants exhibited similar K+-induced folding and end-point structures as indicated by intrinsic fluorescence and circular dichroism, respectively, whereas the polymerization tendencies of the wild-type calsequestrin differed markedly from the polymerization tendencies of the truncation mutants. Static laser light scattering and 3,3′-dithiobis sulfosuccinimidyl-propionate crosslinking indicated that wild-type protein exhibited an initial Ca2+-induced dimerization, followed by additional oligomerization as the Ca2+ concentration was raised or as the K+ concentration was lowered. None of the truncation mutants exhibited clear stepwise oligomerization that depended on increasing Ca2+ concentration. Comparison of the three-dimensional structure of rabbit skeletal calsequestrin with a homology model of canine cardiac calsequestrin from the point of view of our coupled Ca2+ binding and polymerization mechanism leads to a possible explanation for the 2-fold reduced Ca2+ binding capacity of cardiac calsequestrin despite very similar overall net negative charge for the two proteins.

Original languageEnglish (US)
Pages (from-to)16176-16182
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number18
DOIs
StatePublished - May 2 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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