title: Crystal structure of brain-type creatine kinase at 1.41 A resolution.
abstract: Excitable cells and tissues like muscle or brain show a highly fluctuating consumption of ATP, which is efficiently regenerated from a large pool of phosphocreatine by the enzyme creatine kinase (CK). The enzyme exists in tissue--as well as compartment-specific isoforms. Numerous pathologies are related to the CK system: CK is found to be overexpressed in a wide range of solid tumors, whereas functional impairment of CK leads to a deterioration in energy metabolism, which is phenotypic for many neurodegenerative and age-related diseases. The crystal structure of chicken cytosolic brain-type creatine kinase (BB-CK) has been solved to 1.41 A resolution by molecular replacement. It represents the most accurately determined structure in the family of guanidino kinases. Except for the N-terminal region (2-12), the structures of both monomers in the biological dimer are very similar and closely resemble those of the other known structures in the family. Specific Ca2+-mediated interactions, found between two dimers in the asymmetric unit, result in structurally independent heterodimers differing in their N-terminal conformation and secondary structure. The high-resolution structure of BB-CK presented in this work will assist in designing new experiments to reveal the molecular basis of the multiple isoform-specific properties of CK, especially regarding different subcellular locations and functional interactions with other proteins. The rather similar fold shared by all known guanidino kinase structures suggests a model for the transition state complex of BB-CK analogous to the one of arginine kinase (AK). Accordingly, we have modeled a putative conformation of CK in the transition state that requires a rigid body movement of the entire N-terminal domain by rms 4 A from the structure without substrates.
authors.affiliation: Institute of Cell Biology, Swiss Federal Institute of Technology, ETH Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Eder
authors.forename: U
authors.initials: U
authors.lastname: Schlattner
authors.forename: A
authors.initials: A
authors.lastname: Becker
authors.forename: T
authors.initials: T
authors.lastname: Wallimann
authors.forename: W
authors.initials: W
authors.lastname: Kabsch
authors.forename: K
authors.initials: K
authors.lastname: Fritz-Wolf
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000201:enzymology*; D002645:Chickens; D003402:Creatine Kinase / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D003600:Cytosol / Q000201:enzymology; D019281:Dimerization; D007527:Isoenzymes; D008928:Mitochondria / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D015203:Reproducibility of Results
chemical_list: D007527:Isoenzymes; D000255:Adenosine Triphosphate; D003402:Creatine Kinase