Muscle-Type CK MM-CK bound to M- band in myofibril Cardiac tissue: 50% of CK action
Muscle-type CK CK maintains high ATP concentration
Muscle-Type CK Mutation in CK genes linked to myocardial infarction Heart diseases linked to low levels of CK
Brain-Type CK Structure very similar to Muscle-Type CK Most tissues contain MB and BB types High levels in brain, retina, and sperm BB form is the precursor for the other two BB MB MM
Brain-Type CK CK levels associated with learning processes CK overexpressed in tumours Decreased CK neurodegeneration
Mitochondrial CK Bound to outside of inner membrane within cristae Form microcompartments with porins
Mitochondrial CK Transphosphorylation Cr enters through pore Cr + ATP PCr + ADP PCr exits through pore PCr mediates between sites of ATP consumption and production Spatial Energy Buffering
Mi-CK: Octamer stable against denaturation insensitive to proteolysis Dissociation to dimer takes hours to weeks Accelerated with addition of transition state analogue, TSAC = creatine, Mg- ADP & nitrate
Mi-CK: Structure Mi-CK fold differs from all other kinases Structures of Mi-CK-ATP and free enzyme very similar
Mi-CK: Structure Active site residues: Phosphate groups of ATP interact with Arg residues 125, 127, 287, 315 Cys278: substrate binding His61: mutation impairs enzyme activity Loop residues 60-65 moves toward active site for catalysis Trp223: crucial for catalysis
ATP Recycling The PCr circuit: Spatial separation of ATP consumption and synthesis
Mitochondrial VS Cytosolic CK Very similar structures and structural elements Mi-CK evolved different folding pattern for catalyzing phosphoryl transfer Allow compartmentalization of function
References 1. Wallimann T et al. 1998. Some new aspects of creatine kinase (CK): compartmentation, structure, function and regulation for cellular and mitochondrial bioenergetics and physiology. Biofactors 8, 229-234. 2. Schlattner U et al. 1998. Functional aspects of the X-ray structure of mitochondrial creatine kinase: A molecular physiology approach. Molecular and Cellular Biochemistry 184, 125- 140. 3. Yamamichi H et al. 2001. Creatine kinase gene mutation in a patient with muscle creatine kinase deficiency. Clinical Chemistry 47, 1967-1973. 4. Alberts B et al. 1994. Molecular Biology of the Cell, 3 rd edition. New York: Garland Publishing. 5. Lipskaya TY. 2000. The physiological role of the creatine kinase system: evolution of views. Biochemistry (Moscow) 66, 115-129.
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