Document Detail

A bimodular mechanism of calcium control in eukaryotes.
MedLine Citation:
PMID:  23086147     Owner:  NLM     Status:  MEDLINE    
Calcium ions (Ca(2+)) have an important role as secondary messengers in numerous signal transduction processes, and cells invest much energy in controlling and maintaining a steep gradient between intracellular (∼0.1-micromolar) and extracellular (∼2-millimolar) Ca(2+) concentrations. Calmodulin-stimulated calcium pumps, which include the plasma-membrane Ca(2+)-ATPases (PMCAs), are key regulators of intracellular Ca(2+) in eukaryotes. They contain a unique amino- or carboxy-terminal regulatory domain responsible for autoinhibition, and binding of calcium-loaded calmodulin to this domain releases autoinhibition and activates the pump. However, the structural basis for the activation mechanism is unknown and a key remaining question is how calmodulin-mediated PMCA regulation can cover both basal Ca(2+) levels in the nanomolar range as well as micromolar-range Ca(2+) transients generated by cell stimulation. Here we present an integrated study combining the determination of the high-resolution crystal structure of a PMCA regulatory-domain/calmodulin complex with in vivo characterization and biochemical, biophysical and bioinformatics data that provide mechanistic insights into a two-step PMCA activation mechanism mediated by calcium-loaded calmodulin. The structure shows the entire PMCA regulatory domain and reveals an unexpected 2:1 stoichiometry with two calcium-loaded calmodulin molecules binding to different sites on a long helix. A multifaceted characterization of the role of both sites leads to a general structural model for calmodulin-mediated regulation of PMCAs that allows stringent, highly responsive control of intracellular calcium in eukaryotes, making it possible to maintain a stable, basal level at a threshold Ca(2+) concentration, where steep activation occurs.
Henning Tidow; Lisbeth R Poulsen; Antonina Andreeva; Michael Knudsen; Kim L Hein; Carsten Wiuf; Michael G Palmgren; Poul Nissen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-21
Journal Detail:
Title:  Nature     Volume:  491     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-15     Completed Date:  2012-11-30     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  468-72     Citation Subset:  IM    
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MeSH Terms
Amino Acid Sequence
Arabidopsis / chemistry,  enzymology,  metabolism*
Arabidopsis Proteins / chemistry*,  genetics,  metabolism*
Binding Sites
Calcium / metabolism*
Calcium-Transporting ATPases / chemistry*,  genetics,  metabolism*
Calmodulin / chemistry*,  metabolism
Enzyme Activation
Eukaryota / metabolism*
Intracellular Space / chemistry,  metabolism
Models, Molecular
Molecular Sequence Data
Protein Binding
Protein Structure, Tertiary
Sequence Alignment
Grant Support
MC_U105192716//Medical Research Council
Reg. No./Substance:
0/Arabidopsis Proteins; 0/Calmodulin; EC protein, Arabidopsis; EC ATPases; SY7Q814VUP/Calcium

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