Calmodulin complexes with brain and muscle creatine kinase peptides
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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 language | English |
|---|---|
| Journal | Current Research in Structural Biology |
| Volume | 3 |
| Pages (from-to) | 121-132 |
| Number of pages | 12 |
| DOIs | |
| Publication status | Published - 2021 |
Bibliographical note
Funding Information:
The work was supported by funding from the Villum foundation, Denmark (Villum Experiment grant, 17535 to LLL and JS), from the EU ÖKS-interreg project 'Hanseatic League of Science ' (HALOS to JS and LLL, grant UCPH-002) and from the Swedish Research Council ( 2015-00143 to SL). Travel to synchrotrons was supported by the Danish Ministry of Higher Education and Science through the Instrument Center DANSCATT (to LLL). Travel to Lund University (AV and NP) was provided by KINSC, Haverford College, PA, USA. LLL and JS are members of ISBUC, Integrative Structural Biology at the University of Copenhagen ( www.isbuc.ku.dk ). AT acknowledges support from the United States Department of Energy through the Computational Sciences Graduate Fellowship (DOE CSGF) under grant number: DE-SC0019323 . The computational component of the study was supported by the US National Institutes of Health grant P41-GM104601 (to ET).
Funding Information:
The work was supported by funding from the Villum foundation, Denmark (Villum Experiment grant, 17535 to LLL and JS), from the EU ?KS-interreg project 'Hanseatic League of Science' (HALOS to JS and LLL, grant UCPH-002) and from the Swedish Research Council (2015-00143 to SL). Travel to synchrotrons was supported by the Danish Ministry of Higher Education and Science through the Instrument Center DANSCATT (to LLL). Travel to Lund University (AV and NP) was provided by KINSC, Haverford College, PA, USA. LLL and JS are members of ISBUC, Integrative Structural Biology at the University of Copenhagen (www.isbuc.ku.dk). AT acknowledges support from the United States Department of Energy through the Computational Sciences Graduate Fellowship (DOE CSGF) under grant number:DE-SC0019323. The computational component of the study was supported by the US National Institutes of Health grant P41-GM104601 (to ET).
Publisher Copyright:
© 2021 The Author(s)
- Calcium signaling, Calmodulin X-ray structure, Cellular energy metabolism, Enzyme regulation, Isothermal titration calorimetry
Research areas
ID: 299826627