| Structural highlights
Disease
DMPK_HUMAN Defects in DMPK are the cause of dystrophia myotonica type 1 (DM1) [MIM:160900; also known as Steinert disease. A muscular disorder characterized by myotonia, muscle wasting in the distal extremities, cataract, hypogonadism, defective endocrine functions, male baldness and cardiac arrhythmias. Note=The causative mutation is a CTG expansion in the 3'-UTR of the DMPK gene. A length exceeding 50 CTG repeats is pathogenic, while normal individuals have 5 to 37 repeats. Intermediate alleles with 35-49 triplets are not disease-causing but show instability in intergenerational transmissions. Disease severity varies with the number of repeats: mildly affected persons have 50 to 150 repeats, patients with classic DM have 100 to 1,000 repeats, and those with congenital onset can have more than 2,000 repeats.[1] [2] [3] [4]
Function
DMPK_HUMAN Non-receptor serine/threonine protein kinase which is necessary for the maintenance of skeletal muscle structure and function. May play a role in myocyte differentiation and survival by regulating the integrity of the nuclear envelope and the expression of muscle-specific genes. May also phosphorylate PPP1R12A and inhibit the myosin phosphatase activity to regulate myosin phosphorylation. Also critical to the modulation of cardiac contractility and to the maintenance of proper cardiac conduction activity probably through the regulation of cellular calcium homeostasis. Phosphorylates PLN, a regulator of calcium pumps and may regulate sarcoplasmic reticulum calcium uptake in myocytes. May also phosphorylate FXYD1/PLM which is able to induce chloride currents. May also play a role in synaptic plasticity.[5] [6] [7] [8] [9] [10]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
References
- ↑ Fu YH, Pizzuti A, Fenwick RG Jr, King J, Rajnarayan S, Dunne PW, Dubel J, Nasser GA, Ashizawa T, de Jong P, et al.. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science. 1992 Mar 6;255(5049):1256-8. PMID:1546326
- ↑ Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T, et al.. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell. 1992 Feb 21;68(4):799-808. PMID:1310900
- ↑ Jansen G, Mahadevan M, Amemiya C, Wormskamp N, Segers B, Hendriks W, O'Hoy K, Baird S, Sabourin L, Lennon G, et al.. Characterization of the myotonic dystrophy region predicts multiple protein isoform-encoding mRNAs. Nat Genet. 1992 Jul;1(4):261-6. PMID:1302022 doi:http://dx.doi.org/10.1038/ng0792-261
- ↑ Musova Z, Mazanec R, Krepelova A, Ehler E, Vales J, Jaklova R, Prochazka T, Koukal P, Marikova T, Kraus J, Havlovicova M, Sedlacek Z. Highly unstable sequence interruptions of the CTG repeat in the myotonic dystrophy gene. Am J Med Genet A. 2009 Jul;149A(7):1365-74. doi: 10.1002/ajmg.a.32987. PMID:19514047 doi:10.1002/ajmg.a.32987
- ↑ Bush EW, Helmke SM, Birnbaum RA, Perryman MB. Myotonic dystrophy protein kinase domains mediate localization, oligomerization, novel catalytic activity, and autoinhibition. Biochemistry. 2000 Jul 25;39(29):8480-90. PMID:10913253
- ↑ Mounsey JP, John JE 3rd, Helmke SM, Bush EW, Gilbert J, Roses AD, Perryman MB, Jones LR, Moorman JR. Phospholemman is a substrate for myotonic dystrophy protein kinase. J Biol Chem. 2000 Jul 28;275(30):23362-7. PMID:10811636 doi:10.1074/jbc.M000899200
- ↑ Muranyi A, Zhang R, Liu F, Hirano K, Ito M, Epstein HF, Hartshorne DJ. Myotonic dystrophy protein kinase phosphorylates the myosin phosphatase targeting subunit and inhibits myosin phosphatase activity. FEBS Lett. 2001 Mar 30;493(2-3):80-4. PMID:11287000
- ↑ Kaliman P, Catalucci D, Lam JT, Kondo R, Gutierrez JC, Reddy S, Palacin M, Zorzano A, Chien KR, Ruiz-Lozano P. Myotonic dystrophy protein kinase phosphorylates phospholamban and regulates calcium uptake in cardiomyocyte sarcoplasmic reticulum. J Biol Chem. 2005 Mar 4;280(9):8016-21. Epub 2004 Dec 13. PMID:15598648 doi:10.1074/jbc.M412845200
- ↑ Tan I, Lai J, Yong J, Li SF, Leung T. Chelerythrine perturbs lamellar actomyosin filaments by selective inhibition of myotonic dystrophy kinase-related Cdc42-binding kinase. FEBS Lett. 2011 May 6;585(9):1260-8. doi: 10.1016/j.febslet.2011.03.054. Epub, 2011 Mar 30. PMID:21457715 doi:10.1016/j.febslet.2011.03.054
- ↑ Harmon EB, Harmon ML, Larsen TD, Yang J, Glasford JW, Perryman MB. Myotonic dystrophy protein kinase is critical for nuclear envelope integrity. J Biol Chem. 2011 Nov 18;286(46):40296-306. doi: 10.1074/jbc.M111.241455. Epub, 2011 Sep 26. PMID:21949239 doi:10.1074/jbc.M111.241455
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