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== Introduction == | == Introduction == | ||
All living organisms depend on P-type ATPase to pump cation across the membrane. They play a fundamental role in their metabolism and physiology. Ca2+ ATPase, a P-type ATPase, transports calcium ions across the membrane against a concentration gradient. These pumps clear cytoplasm of the second messenger, the calcium. It's very important to keep a low concentration of calcium in the cell for a good cell signaling. | All living organisms depend on P-type ATPase to pump cation across the membrane. They play a fundamental role in their metabolism and physiology. Ca2+ ATPase, a P-type ATPase, transports calcium ions across the membrane against a concentration gradient. These pumps clear cytoplasm of the second messenger, the calcium. It's very important to keep a low concentration of calcium in the cell for a good cell signaling. | ||
Revision as of 18:06, 1 January 2015
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Contents |
Introduction
All living organisms depend on P-type ATPase to pump cation across the membrane. They play a fundamental role in their metabolism and physiology. Ca2+ ATPase, a P-type ATPase, transports calcium ions across the membrane against a concentration gradient. These pumps clear cytoplasm of the second messenger, the calcium. It's very important to keep a low concentration of calcium in the cell for a good cell signaling. We can found the PMCA (Plasma Membrane Ca2+ ATPase) which remove the calcium from the cell and the SERCA (Sarcoplasmic Endoplasmic Reticulum Ca2+ ATPase) which pumps calcium into the endoplasmique reticulum. The hydrolysis of one adenosine triphosphate (ATP) is essential for the functioning of the pump and the transport of one calcium ion.
Structural highlights
Ligand and interaction
The architecture of calcium ATPase (determined by X-Ray crystallography) allow to understand mechanisms by which the energy of ATP is coupled to the calcium transport across a membrane. Structurally, the pump contains 10 transmembrane domains (α helices), two large intracellular loops and amino/carboxy-terminal cytoplasmic tails. In the cytoplasm, the ATP binds to the cytosolic loop that connects transmembrane domains four and five (ATP binding site). It transfers its γ-phosphate to the aspartic acide 351 (phosphorylation site) and creates a acid-stable aspartyl phosphate intermediate. The binding of ATP is initiated by the cooperative fixing of two calcium ions to the transport site. The phosphorylation of Asp351 allows a large conformational changes in cytoplasmic domains which closes the ion gates from the cytoplasm and alters the affinity of the protein for the calcium. After releasing calcium (in the lumen of cytoplasm or out side the cell), two protons are bound to the transport sites (charges compensation) and the aspartyl phosphate is hydrolyzed to complete the cycle. To sum up, calcium pumps have two conformations, E1 and E2. E1 has the calcium binding site oriented toward the cytoplasm . E2 has the calcium binding site oriented toward the lumen of the endoplasmic reticulum or toward the extracellular background. These two conformations are characterized by different specificity for ion binding.
Regulations
There are different kind of calcium ATPase regulations. For example, the phospholamban (PLN or PLB) is a membrane protein that regulates the calcium pump in cardiac muscle and skeletal muscle cells. This small phosphoprotein is a pentamer. The phospholamban can be phosphorylated at three distinct sites by various protein kinases (PKA, PKC, CamK...). The phosphorylation state is mediatedthrough beta-adrenergic stimulation. In unphosphorylate state, the phospholamban inhibits the activity of calcium pump in cardiac and skeletal muscle cells by decreasing the apparent affinity of the ATPase for calcium. The phosphorylation of the protein results in the dissociation of the protein from the ATPase. The phosphoprotein binds just downstream of the active ATPase site (asp351). The activity of the calcium pump is also regulated by by calmodulin, acidic phospholipids and phosphorylation by kinases A and C. Most of the activation mechanisms implicate the C-terminal region of the pump containing the high affinity calmodulin binding domain, which is involved in the autoinhibition of the pump.
Dysfunctions and diseases
References
David H.MacLennan, William J.Rice and N. Michael Green, 1997 - The Mechanism of Ca2+ Transport by Sarco(Endo)plasmic Reticulum Ca2+-ATPases - The Journal of Biological Chemistry, p.272, 28815-28818
Marianela G.Dalghi, Marisa M.Fernández, Mariela Ferreira-Gomes, Irene C.Mangialavori, Emilio L.Malchiodi, Emanuel E.Strehler and Juan Pablo F.C.Rossi, 2013 - Plasma Membrane Calcium ATPase Activity Is Regulated by Actin Oligomers through Direct Interaction - The Journal of Biological Chemistry, p.288, 23380-23393
Marisa Brini and Ernesto Carafoli, 2010 - The Plasma Membrane Ca2+ ATPase and the Plasma Membrane Sodium Calcium Exchanger Cooperate in the Regulation of Cell Calcium - Cold Spring Harbor Perspectives in Biology
Thomas D.Pollard and William C. Earnshaw, - - Cell Biology (second edition), p.
