Janina Sprenger, Anda Trifan, Neal Patel, Ashley Vanderbeck, Jenny Bredtfelt,
Emad Tajkhorshid, Roger Rowlett, Leila Lo Leggio, Karin S. Åkerfeldt, and
Sara Linse.
Calmodulin complexes with brain and muscle creatine kinase peptides.
Current Research in Structural Biology, 3:121-132, 2021.
SPRE2021-ET
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 Åand 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.
