The structural basis of calcium transport by the calcium pump

• Published in: Nature Vol. 450; no. 7172; pp. 1036 - 1042
• Main Authors: Møller, Jesper Vuust, Gyrup, Claus, Picard, Martin, Nissen, Poul, Olesen, Claus, Winther, Anne-Marie Lund, Morth, J. Preben, Oxvig, Claus
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 13-12-2007; Nature Publishing Group
• Subjects: Adenosine triphosphatase; Adenosine Triphosphate - metabolism; Aluminum; Animals; ATP; Beryllium; Binding sites; Biological and medical sciences; Calcium; Calcium - metabolism; Cellular biology; Crystal structure; Crystalline structure; Crystallography, X-Ray; Electrochemistry; Fluorides; Fundamental and applied biological sciences. Psychology; Ion Transport; Mass Spectrometry; Metabolism; Models, Molecular; Molecular biology; Molecular biophysics; Muscle, Skeletal - enzymology; Muscle, Skeletal - metabolism; Phosphorylation; Protein Conformation; Pumps; Rabbits; Sarcoplasmic Reticulum Calcium-Transporting ATPases - chemistry; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Structure in molecular biology; Structure-Activity Relationship; Thapsigargin; Translocation; Enzyme; Rabbit; Lagomorpha; Striated muscle; Structure function relationship; transporting ATPase; Vertebrata; Mammalia; Three dimensional structure; Hydrolases; Sarcoplasm; Ca; Crystalline structure
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature06418

The sarcoplasmic reticulum Ca2+-ATPase, a P-type ATPase, has a critical role in muscle function and metabolism. Here we present functional studies and three new crystal structures of the rabbit skeletal muscle Ca2+-ATPase, representing the phosphoenzyme intermediates associated with Ca2+ binding, Ca2+ translocation and dephosphorylation, that are based on complexes with a functional ATP analogue, beryllium fluoride and aluminium fluoride, respectively. The structures complete the cycle of nucleotide binding and cation transport of Ca2+-ATPase. Phosphorylation of the enzyme triggers the onset of a conformational change that leads to the opening of a luminal exit pathway defined by the transmembrane segments M1 through M6, which represent the canonical membrane domain of P-type pumps. Ca2+ release is promoted by translocation of the M4 helix, exposing Glu 309, Glu 771 and Asn 796 to the lumen. The mechanism explains how P-type ATPases are able to form the steep electrochemical gradients required for key functions in eukaryotic cells.