4AQR

Crystal structure of calmodulin in complex with the regulatory domain of a plasma-membrane Ca2+-ATPase

Summary for 4AQR

• Entry DOI: 10.2210/pdb4aqr/pdb
• Descriptor: CALMODULIN-7, CALCIUM-TRANSPORTING ATPASE 8, PLASMA MEMBRANE-TYPE, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: ca-binding protein-hydrolase complex, plasma-membrane calcium atpase, ca-binding protein/hydrolase
• Biological source: ARABIDOPSIS THALIANA; More
• Cellular location: Cell membrane; Multi-pass membrane protein: Q9LF79
• Total number of polymer chains: 3
• Total formula weight: 40963.95

Authors

Tidow, H.,Poulsen, L.R.,Andreeva, A.,Hein, K.L.,Palmgren, M.G.,Nissen, P. (deposition date: 2012-04-19, release date: 2012-10-17, Last modification date: 2024-05-08)

Primary citation

Tidow, H.,Poulsen, L.R.,Andreeva, A.,Knudsen, M.,Hein, K.L.,Wiuf, C.,Palmgren, M.G.,Nissen, P.
A Bimodular Mechanism of Calcium Control in Eukaryotes
Nature, 491:468-, 2012

PubMed Abstract: 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.

PubMed: 23086147
DOI: 10.1038/NATURE11539

Experimental method

X-RAY DIFFRACTION (1.95 Å)