Dystrophia myotonica protein kinase (DMK) is an enzyme that in humans is encoded by the DMPK gene. The DMPK gene product is a Ser/Thr protein kinase homologous to MRCK p21-activated kinase and Rho kinase family. The kinase is present both in membrane-bound and soluble form in human left ventricular samples. DMPK substrates proposed in in vitro studies include phospholipids, dihydropyridine receptors, and myosin phosphatase targeting subunits. However, in vivo methods for demonstrating DMPK phosphorylation of these substrates need to be established, and the link between these substrates and clinical manifestations of tonic dystrophy (DM) is unclear.
Structures
Muscular dystrophy protein kinase (DMPK) consists of a kinase domain and a coiled-coil domain involved in multimerization. The crystal structure of the DMPK kinase domain combined with the inhibitor bisindolylmaleimide VIII (BIM-8) reveals a dimerase associated with a conserved dimerization domain. The kinase domain is not sufficient for dimerization in vivo, and the coiled-coil domain is necessary for stable dimer formation. The kinase domain is in an active conformation, has a fully ordered and correctly positioned aC helix, and the catalytic residues are in a conformation capable of catalysis. Although not phosphorylated, a conserved hydrophobic motif at the C-terminal extension of the kinase domain binds to the N-terminal leaf of the kinase domain.
Functions
Muscular dystrophy protein kinase (DMPK) is closely related to other kinases that interact with members of the Rho family of small GTPases. Substrates of this enzyme include myogenin, the beta subunit of L-type calcium channels, and phosphorylated lemman. The protein may be involved in intracellular communication. It also seems to regulate the production and function of important structures inside muscle cells by interacting with other proteins. For example, tonic muscle dystrophin protein kinase has been shown to turn off (inhibit) the portion of muscle protein called myosin phosphatase. Myosin phosphatase plays a role in muscle tightening (contraction) and relaxation.
Diseases
Muscular dystrophy protein kinase (DMPK) is an autosomal dominant multi-system disease characterized by progressive muscle weakness, muscular atrophy, and muscular rigidity. The disease includes type 1 caused by mutations in the tonic muscular dystrophy protein kinase gene (DMPK) and type 2 caused by mutations in the cellular nucleic acid binding protein gene (CNBP). Among them, type 1 is the most common muscular dystrophy in adults, and the incidence is about 1/8000～1/7000. Type 2 is rare. On May 11, 2018, the National Health Commission and other five departments jointly formulated the "First Batch of Rare Diseases", and ankylosing muscular dystrophy was included.
Clinical manifestation
Muscular dystrophy protein kinase (DMPK) usually develops during adolescence. The first symptom is stiff muscles in the hands, manifested as laborious release of hands after fisting, and with the weakness of the hand muscles, facial muscle rigidity manifests as forcefully closing the eyes and not opening the eyes quickly. With the development of the disease, forearm and hand muscle atrophy, calf muscle weakness and atrophy cause the foot to sag, and the toe is lifted when walking. The atrophy of the facial muscles, masseter muscles, and temporal muscles leads to a long and thin face, which looks like an axe, hence the name "axe-shaped face". The weakness of the neck muscles makes it difficult to lie down in the supine position. Some patients have difficulty speaking and swallowing due to weakness and rigidity of the tongue and throat muscles. Tonic muscle dystrophy type 2 is more common in women with relatively mild symptoms. The first symptom is weakness in the proximal limbs, followed by hand stiffness and muscle pain. Patients with early onset are more likely to show signs of involvement in other systems. Endocrine abnormalities can be seen in diabetes, hypothyroidism and excessive sleep, men with hair loss and impotence, women with irregular menstruation, infertility or habitual abortion. In the late stage of the disease, heart damage occurs with palpitation, chest tightness and shortness of breath, and arrhythmia occurs in severe cases; cataracts in the eyes cause vision loss; constipation in gastrointestinal smooth muscle dysfunction; constipation in the central nervous system leads to cognitive impairment and depression.
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