Structural basis for activation of calcineurin by calmodulin

Julie Rumi-Masante, Farai I. Rusinga, Terrence E. Lester, Tori B. Dunlap, Todd D. Williams, A. Dunker, David D. Weis, Trevor P. Creamer

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The highly conserved phosphatase calcineurin (CaN) plays vital roles in numerous processes including T-cell activation, development and function of the central nervous system, and cardiac growth. It is activated by the calcium sensor calmodulin (CaM). CaM binds to a regulatory domain (RD) within CaN, causing a conformational change that displaces an autoinhibitory domain (AID) from the active site, resulting in activation of the phosphatase. This is the same general mechanism by which CaM activates CaM-dependent protein kinases. Previously published data have hinted that the RD of CaN is intrinsically disordered. In this work, we demonstrate that the RD is unstructured and that it folds upon binding CaM, ousting the AID from the catalytic site. The RD is 95 residues long, with the AID attached to its C-terminal end and the 24-residue CaM binding region toward the N-terminal end. This is unlike the CaM-dependent protein kinases that have CaM binding sites and AIDs immediately adjacent in sequence. Our data demonstrate that not only does the CaM binding region folds but also an ∼ 25- to 30-residue region between it and the AID folds, resulting in over half of the RD adopting α-helical structure. This appears to be the first observation of CaM inducing folding of this scale outside of its binding site on a target protein.

Original languageEnglish
Pages (from-to)307-317
Number of pages11
JournalJournal of Molecular Biology
Volume415
Issue number2
DOIs
StatePublished - Jan 13 2012

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Calcineurin
Calmodulin
Calcium-Calmodulin-Dependent Protein Kinases
Catalytic Domain
Binding Sites
Phosphoric Monoester Hydrolases
Central Nervous System
Observation
Calcium
T-Lymphocytes
Growth

Keywords

  • folding
  • intrinsically disordered protein
  • phosphatase

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Rumi-Masante, J., Rusinga, F. I., Lester, T. E., Dunlap, T. B., Williams, T. D., Dunker, A., ... Creamer, T. P. (2012). Structural basis for activation of calcineurin by calmodulin. Journal of Molecular Biology, 415(2), 307-317. https://doi.org/10.1016/j.jmb.2011.11.008

Structural basis for activation of calcineurin by calmodulin. / Rumi-Masante, Julie; Rusinga, Farai I.; Lester, Terrence E.; Dunlap, Tori B.; Williams, Todd D.; Dunker, A.; Weis, David D.; Creamer, Trevor P.

In: Journal of Molecular Biology, Vol. 415, No. 2, 13.01.2012, p. 307-317.

Research output: Contribution to journalArticle

Rumi-Masante, J, Rusinga, FI, Lester, TE, Dunlap, TB, Williams, TD, Dunker, A, Weis, DD & Creamer, TP 2012, 'Structural basis for activation of calcineurin by calmodulin', Journal of Molecular Biology, vol. 415, no. 2, pp. 307-317. https://doi.org/10.1016/j.jmb.2011.11.008
Rumi-Masante J, Rusinga FI, Lester TE, Dunlap TB, Williams TD, Dunker A et al. Structural basis for activation of calcineurin by calmodulin. Journal of Molecular Biology. 2012 Jan 13;415(2):307-317. https://doi.org/10.1016/j.jmb.2011.11.008
Rumi-Masante, Julie ; Rusinga, Farai I. ; Lester, Terrence E. ; Dunlap, Tori B. ; Williams, Todd D. ; Dunker, A. ; Weis, David D. ; Creamer, Trevor P. / Structural basis for activation of calcineurin by calmodulin. In: Journal of Molecular Biology. 2012 ; Vol. 415, No. 2. pp. 307-317.
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