Biology:Myotonin-protein kinase

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

Myotonin-protein kinase (MT-PK) also known as myotonic dystrophy protein kinase (MDPK) or dystrophia myotonica protein kinase (DMPK) is an enzyme that in humans is encoded by the DMPK gene.

The dmpk gene product is a Ser/Thr protein kinase homologous to the MRCK p21-activated kinases and Rho kinase family. Data obtained by using antibodies that detect specific isoforms of DMPK indicate that the most abundant isoform of DMPK is an 80-kDa protein expressed almost exclusively in smooth, skeletal, and cardiac muscles. This kinase exists both as a membrane-associated and as a soluble form in human left ventricular samples. The different C termini of DMPK that arise from alternative splicing determine its localization to the endoplasmic reticulum, mitochondria, or cytosol in transfected COS-1 cells. Among the substrates for DMPK proposed by in vitro studies are phospholemman, the dihydropyridine receptor, and the myosin phosphatase targeting subunit. However, an in vivo demonstration of the phosphorylation of these substrates by DMPK remains to be established, and a link between these substrates and the clinical manifestations of myotonic dystrophy (DM) is unclear.

Function

Myotonin-protein kinase is a serine-threonine kinase that is closely related to other kinases that interact with members of the Rho family of small GTPases. Substrates for this enzyme include myogenin, the beta-subunit of the L-type calcium channels, and phospholemman. Although the specific function of this protein is unknown, it appears to play an important role in muscle, heart, and brain cells. This protein may be involved in communication within cells. It also appears to regulate the production and function of important structures inside muscle cells by interacting with other proteins. For example, myotonic dystrophy protein kinase has been shown to turn off (inhibit) part of a muscle protein called myosin phosphatase. Myosin phosphatase is an enzyme that plays a role in muscle tensing (contraction) and relaxation.

Structure

Dystrophia myotonica protein kinase (DMPK) is a serine/threonine kinase composed of a kinase domain and a coiled-coil domain involved in the multimerization. The crystal structure of the kinase domain of DMPK bound to the inhibitor bisindolylmaleimide VIII (BIM-8) revealed a dimeric enzyme associated by a conserved dimerization domain. The affinity of dimerisation suggested that the kinase domain alone is insufficient for dimerisation in vivo and that the coiled-coil domains are required for stable dimer formation. The kinase domain is in an active conformation, with a fully ordered and correctly positioned aC helix, and catalytic residues in a conformation competent for catalysis. The conserved hydrophobic motif at the C-terminal extension of the kinase domain is bound to the N-terminal lobe of the kinase domain, despite being unphosphorylated.

Clinical significance

The 3' untranslated region of this gene contains 5-37 copies of a CTG trinucleotide repeat. Expansion of this unstable motif to 50-5,000 copies causes myotonic dystrophy type I, which increases in severity with increasing repeat element copy number. Repeat expansion is associated with condensation of local chromatin structure that disrupts the expression of genes in this region. As the DMPK repeat is replicated, the hairpin loop that is formed leads to repeat expansion (a) or contractions (b).

CTG repeats are located in the 3' UTR of the DMPK gene. Through formation of hairpin loops, the repeats are contracted or expanded.

Myotonic dystrophy (DM) 1 is an autosomal dominant neuromuscular disorder affecting approximately 1 in 8000 individuals. Affected individuals display a wide range of symptoms including myotonia, skeletal muscle weakness and wasting, cardiac conduction abnormalities, and cataracts. Despite cloning of the locus, the complex disease phenotype of DM has proven difficult to interpret, and the exact role of DMPK in the pathogenesis of DM remains unclear.

Interactions

Myotonic dystrophy protein kinase has been shown to interact with HSPB2 and RAC1.

Regulation

The close relationship of DMPK to the Rho-kinases has led to speculation whether DMPK activity may be regulated in vivo by small G proteins, particularly of the Rho family. Although DMPK lacks obvious binding sites for known G, DMPK-1 oligomers exhibit low basal catalytic activity due to the presence of the C-terminal autoinhibitory domain (AI). A protease (P) within the membrane cleaves DMPK-1, removing the C-terminal autoinhibitory and membrane association domains and releasing cytosolic, basally active DMPK-2. This processing event would produce longterm activation of the kinase. Short-term activation of DMPK-1 and -2 may be mediated by transitory interaction with a small GTPase (G).

A general model that accounts for DMPK oligomerization, processing, and regulation has been proposed. In this model, transient activation of kinase activity would occur in response to G protein second messengers, while longterm activation of DMPK could be mediated by a membrane associated protease that cleaves DMPK-1 to release cytosolic DMPK-2 in a persistently activated form. The persistent activation of serine/threonine kinases has been shown to play a role in the determination of cell fate as well as memory production in the nervous system. In this respect, DMPK may be similar to PKA and PKC, two kinases that can be transiently activated in response to second messengers or persistently activated by proteolytic removal of an autoinhibitory domain. Thus, this model suggests that the two endogenous DMPK forms may possess different activities, localizations, regulators, and substrates and perform distinct physiological functions.

Further reading

• "Expanding complexity in myotonic dystrophy". BioEssays 20 (11): 901–12. November 1998. doi:10.1002/(SICI)1521-1878(199811)20:11<901::AID-BIES5>3.0.CO;2-0. PMID 9872056. 
• "Characterization of the myotonic dystrophy region predicts multiple protein isoform-encoding mRNAs". Nature Genetics 1 (4): 261–6. July 1992. doi:10.1038/ng0792-261. PMID 1302022. 
• "Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy". Nature Genetics 1 (3): 192–5. June 1992. doi:10.1038/ng0692-192. PMID 1303233. 
• "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 68 (4): 799–808. February 1992. doi:10.1016/0092-8674(92)90154-5. PMID 1310900. 
• "Localisation of the myotonic dystrophy locus to 19q13.2-19q13.3 and its relationship to twelve polymorphic loci on 19q". Human Genetics 87 (1): 73–80. May 1991. doi:10.1007/BF01213096. PMID 2037285. 
• "Different expression of the myotonin protein kinase gene in discrete areas of human brain". Biochemical and Biophysical Research Communications 216 (2): 489–94. November 1995. doi:10.1006/bbrc.1995.2649. PMID 7488138. 
• "Genomic organization and transcriptional units at the myotonic dystrophy locus". Genomics 18 (3): 673–9. December 1993. doi:10.1016/S0888-7543(05)80372-6. PMID 7905855. 
• "Expression of a novel human myotonin protein kinase (MtPK) cDNA clone which encodes a protein with a thymopoietin-like domain in COS cells". FEBS Letters 351 (1): 22–6. August 1994. doi:10.1016/0014-5793(94)00808-6. PMID 8076686. 
• "Myotonic dystrophy kinase is a component of neuromuscular junctions". Human Molecular Genetics 2 (11): 1889–94. November 1993. doi:10.1093/hmg/2.11.1889. PMID 8281152. 
• "Absence of myotonic dystrophy protein kinase (DMPK) mRNA as a result of a triplet repeat expansion in myotonic dystrophy". Genomics 18 (2): 340–8. November 1993. doi:10.1006/geno.1993.1474. PMID 8288237. 
• "No imprinting involved in the expression of DM-kinase mRNAs in mouse and human tissues". Human Molecular Genetics 2 (8): 1221–7. August 1993. doi:10.1093/hmg/2.8.1221. PMID 8401505. 
• "Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy". Science 260 (5105): 235–8. April 1993. doi:10.1126/science.8469976. PMID 8469976. Bibcode: 1993Sci...260..235F. 
• "Structure and genomic sequence of the myotonic dystrophy (DM kinase) gene". Human Molecular Genetics 2 (3): 299–304. March 1993. doi:10.1093/hmg/2.3.299. PMID 8499920. 
• "A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat". Human Molecular Genetics 4 (10): 1919–25. October 1995. doi:10.1093/hmg/4.10.1919. PMID 8595416. 
• "Altered phosphorylation and intracellular distribution of a (CUG)n triplet repeat RNA-binding protein in patients with myotonic dystrophy and in myotonin protein kinase knockout mice". Proceedings of the National Academy of Sciences of the United States of America 94 (24): 13221–6. November 1997. doi:10.1073/pnas.94.24.13221. PMID 9371827. Bibcode: 1997PNAS...9413221R. 
• "MKBP, a novel member of the small heat shock protein family, binds and activates the myotonic dystrophy protein kinase". The Journal of Cell Biology 140 (5): 1113–24. March 1998. doi:10.1083/jcb.140.5.1113. PMID 9490724. 
• "Localization of myotonic dystrophy protein kinase in human and rabbit tissues using a new panel of monoclonal antibodies". Human Molecular Genetics 7 (12): 1957–65. November 1998. doi:10.1093/hmg/7.12.1957. PMID 9811941. 

External links

• GeneReviews/NCBI/NIH/UW entry on Myotonic Dystrophy Type 1