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Homodimerization through coiled-coil regions enhances activity of the myotonic dystrophy protein kinase.

Zhang R., Epstein H.F.

Myotonic dystrophy protein kinase (DMPK) is the protein product of the human DM-1 locus on chromosome 19q13.1 and has been implicated in the cardiac and behavioral dysfunctions of the disorder. DMPK contains four distinct regions: a leucine-rich repeat (L), a serine-threonine protein kinase catalytic domain (PK), an alpha-helical coiled-coil region (H), and a putative transmembrane-spanning tail (T). Multiple protein kinases that participate in cytoskeletal and cell cycle functions share homology with DMPK in the PK and H regions. Here we show that the LPKH and PKH subfragments of DMPK formed dimers of 140000 molecular weight, whereas the LPK subfragment remained a monomer of 62000 apparent molecular weight. The H domain thus appeared to be required for dimerization of DMPK subfragments. Caspase 1 cleaved LPKH between the PK and H regions. After cleavage, LPKH dimers became LPK-like monomers, consistent with the H domain mediating dimerization. The V(max) and k(cat)/K(m) of LPKH with a synthetic peptide kinase substrate were over 10-fold greater than either LPK or caspase-cleaved LPKH. The K(m) of dimeric LPKH was over three-fold greater than those of the monomeric proteins. Dimerization appeared to significantly affect the catalytic efficiency and substrate binding of DMPK. These interactions are likely to be functionally significant in other members of the myotonic dystrophy family of protein kinases with extensive coiled-coil domains.

FEBS Lett. 546:281-287(2003) [PubMed] [Europe PMC]

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