Key result
The relevant epitopes determining the isoenzyme-specific targeting of muscle-type and brain-type creatine kinase in skeletal muscle are entirely located within their N-terminal regions.
The N-terminal region (residues 1-234) of cytosolic creatine kinase isoforms determines their isoenzyme-specific targeting to the sarcomeric M-band or I-band in skeletal muscle.
N-terminal CK targeting may enable isoform-specific muscle interventions; leaves open translation from animal models to clinical use.
The molecular origin of the isoenzyme-specific interaction of cytosolic creatine kinase isoenzymes, muscle-type creatine kinase and brain-type creatine kinase, with myofibrillar structures has been studied by confocal microscopy in an functional in situ binding assay with chemically skinned, unfixed skeletal muscle fibers using wild-type and chimeric creatine kinase isoproteins. The specific interaction of both wild-type isoforms with the sarcomeric structure resulted in a stable, isoform-characteristic labeling pattern with muscle-type creatine kinase bound exclusively and tightly to the sarcomeric M-band while brain-type creatine kinase was confined to the I-band region. Chimeric proteins of both muscle-type and brain-type creatine kinases were constructed to localize the corresponding binding domain(s). Exchanged domains included the N-terminal part (residues 1-234), the region containing an isoenzyme 'diagnostic box' (residues 235-285) and the C-terminal part (residues 286-380). The purified recombinant proteins were all fully intact and enzymatically active. All chimeric proteins containing the N-terminal region (amino acid 1-234) of muscle-type or brain-type creatine kinase were always specifically targeted to the sarcomeric M-band or I-band, respectively. We therefore propose that the relevant epitope(s), determining the isoenzyme-specific targeting in skeletal muscle, are entirely located within the N-terminal regions of both cytosolic creatine kinase isoforms.
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Stolz et al. (1998) studied this question. Chimeric creatine kinase isoproteins was evaluated on Localization of binding domains. The relevant epitopes determining the isoenzyme-specific targeting of muscle-type and brain-type creatine kinase in skeletal muscle are entirely located within their N-terminal regions.
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