Calmodulin complexes with brain and muscle creatine kinase peptides

Janina Sprenger, Anda Trifan, Neal Patel, Ashley Vanderbeck, Jenny Bredfelt, Emad Tajkhorshid, Roger Rowlett, Leila Lo Leggio, Karin S. Åkerfeldt, Sara Linse

Research output: Contribution to journalArticlepeer-review


Calmodulin (CaM) is a ubiquitous Ca2+ sensing protein that binds to and modulates numerous target proteins and enzymes during cellular signaling processes. A large number of CaM-target complexes have been identified and structurally characterized, revealing a wide diversity of CaM-binding modes. A newly identified target is creatine kinase (CK), a central enzyme in cellular energy homeostasis. This study reports two high-resolution X-ray structures, determined to 1.24 ​Å and 1.43 ​Å resolution, of calmodulin in complex with peptides from human brain and muscle CK, respectively. Both complexes adopt a rare extended binding mode with an observed stoichiometry of 1:2 CaM:peptide, confirmed by isothermal titration calorimetry, suggesting that each CaM domain independently binds one CK peptide in a Ca2+-depended manner. While the overall binding mode is similar between the structures with muscle or brain-type CK peptides, the most significant difference is the opposite binding orientation of the peptides in the N-terminal domain. This may extrapolate into distinct binding modes and regulation of the full-length CK isoforms. The structural insights gained in this study strengthen the link between cellular energy homeostasis and Ca2+-mediated cell signaling and may shed light on ways by which cells can ‘fine tune’ their energy levels to match the spatial and temporal demands.

Original languageEnglish (US)
Pages (from-to)121-132
Number of pages12
JournalCurrent Research in Structural Biology
StatePublished - Jan 2021


  • Calcium signaling
  • Calmodulin X-ray structure
  • Cellular energy metabolism
  • Enzyme regulation
  • Isothermal titration calorimetry

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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