Myotonin-protein kinase

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Dystrophia myotonica-protein kinase
PBB Protein DMPK image.jpg
PDB rendering based on 1wt6.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols DMPK ; DM; DM1; DM1PK; DMK; MDPK; MT-PK
External IDs OMIM605377 MGI94906 HomoloGene3247 IUPHAR: 1505 ChEMBL: 5320 GeneCards: DMPK Gene
EC number 2.7.11.1
RNA expression pattern
PBB GE DMPK 37996 s at tn.png
PBB GE DMPK 217066 s at tn.png
PBB GE DMPK 217661 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1760 13400
Ensembl ENSG00000104936 ENSMUSG00000030409
UniProt Q09013 P54265
RefSeq (mRNA) NM_001081560 NM_001190490
RefSeq (protein) NP_001075029 NP_001177419
Location (UCSC) Chr 19:
45.77 – 45.78 Mb
Chr 7:
19.08 – 19.09 Mb
PubMed search [1] [2]

Myotonin-protein kinase (MT-PK) also known as myotonic dystrophy protein kinase (MDPK) or dystrophia myotonica protein kinase (DMK) is an enzyme that in humans is encoded by the DMPK gene.[1][2][3]

The dmpk gene product is a Ser/Thr protein kinase homologous to the MRCK p21-activated kinases and the Rho family of kinases.[4] 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.[5] 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.[6] ). 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 DM is unclear.[7][8]

Function[edit]

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.[3] 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.[9]

Structure[edit]

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.[10]

Clinical significance[edit]

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 shown in the figure, as the DMPK repeat is replicated, the hairpoon loop that is formed leads to repeat expansion (a) or contractions (b).[3]

CTG repeats are located in the 3' UTR of the DMPK gene. Through formation of hairpoon 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.[11]

Interactions[edit]

Myotonic dystrophy protein kinase has been shown to interact with HSPB2[12][13] and RAC1.[14]

Regulation[edit]

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 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.[15][16]

References[edit]

  1. ^ Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G et al. (April 1992). "Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene". Science 255 (5049): 1253–5. doi:10.1126/science.1546325. PMID 1546325. 
  2. ^ Fu YH, Pizzuti A, Fenwick RG, King J, Rajnarayan S, Dunne PW et al. (April 1992). "An unstable triplet repeat in a gene related to myotonic muscular dystrophy". Science 255 (5049): 1256–8. doi:10.1126/science.1546326. PMID 1546326. 
  3. ^ a b c "Entrez Gene: DMPK dystrophia myotonica-protein kinase". 
  4. ^ Amano M, Chihara K, Nakamura N, Kaneko T, Matsuura Y, Kaibuchi K (Nov 1999). "The COOH terminus of Rho-kinase negatively regulates rho-kinase activity". The Journal of Biological Chemistry 274 (45): 32418–24. doi:10.1074/jbc.274.45.32418. PMID 10542285. 
  5. ^ Lam LT, Pham YC, Nguyen TM, Morris GE (Sep 2000). "Characterization of a monoclonal antibody panel shows that the myotonic dystrophy protein kinase, DMPK, is expressed almost exclusively in muscle and heart". Human Molecular Genetics 9 (14): 2167–73. doi:10.1093/hmg/9.14.2167. PMID 10958655. 
  6. ^ Wansink DG, van Herpen RE, Coerwinkel-Driessen MM, Groenen PJ, Hemmings BA, Wieringa B (Aug 2003). "Alternative splicing controls myotonic dystrophy protein kinase structure, enzymatic activity, and subcellular localization". Molecular and Cellular Biology 23 (16): 5489–501. doi:10.1128/mcb.23.16.5489-5501.2003. PMID 12897125. 
  7. ^ Timchenko L, Nastainczyk W, Schneider T, Patel B, Hofmann F, Caskey CT (Jun 1995). "Full-length myotonin protein kinase (72 kDa) displays serine kinase activity". Proceedings of the National Academy of Sciences of the United States of America 92 (12): 5366–70. doi:10.1073/pnas.92.12.5366. PMID 7777513. 
  8. ^ Kaliman P, Catalucci D, Lam JT, Kondo R, Gutiérrez JC, Reddy S et al. (Mar 2005). "Myotonic dystrophy protein kinase phosphorylates phospholamban and regulates calcium uptake in cardiomyocyte sarcoplasmic reticulum". The Journal of Biological Chemistry 280 (9): 8016–21. doi:10.1074/jbc.M412845200. PMID 15598648. 
  9. ^ http://ghr.nlm.nih.gov/gene/DMPK.  Missing or empty |title= (help)
  10. ^ Elkins JM, Amos A, Niesen FH, Pike AC, Fedorov O, Knapp S (Apr 2009). "Structure of dystrophia myotonica protein kinase". Protein Science 18 (4): 782–91. doi:10.1002/pro.82. PMID 19309729. 
  11. ^ Bush, Eric W. (May 9, 2000). "Myotonic Dystrophy Protein Kinase Domains Mediate Localization, Oligomerization, Novel Catalytic Activity, and Autoinhibition". Biochemistry 39: 8480–8490. doi:10.1021/bi992142f. 
  12. ^ Suzuki A, Sugiyama Y, Hayashi Y, Nyu-i N, Yoshida M, Nonaka I et al. (March 1998). "MKBP, a novel member of the small heat shock protein family, binds and activates the myotonic dystrophy protein kinase". J. Cell Biol. (UNITED STATES) 140 (5): 1113–24. doi:10.1083/jcb.140.5.1113. ISSN 0021-9525. PMC 2132705. PMID 9490724. 
  13. ^ Sugiyama Y, Suzuki A, Kishikawa M, Akutsu R, Hirose T, Waye MM et al. (January 2000). "Muscle develops a specific form of small heat shock protein complex composed of MKBP/HSPB2 and HSPB3 during myogenic differentiation". J. Biol. Chem. 275 (2): 1095–104. doi:10.1074/jbc.275.2.1095. PMID 10625651. 
  14. ^ Shimizu M, Wang W, Walch ET, Dunne PW, Epstein HF (June 2000). "Rac-1 and Raf-1 kinases, components of distinct signaling pathways, activate myotonic dystrophy protein kinase". FEBS Lett. 475 (3): 273–7. doi:10.1016/S0014-5793(00)01692-6. PMID 10869570. 
  15. ^ Bush EW, Helmke SM, Birnbaum RA, Perryman MB (Jul 2000). "Myotonic dystrophy protein kinase domains mediate localization, oligomerization, novel catalytic activity, and autoinhibition". Biochemistry 39 (29): 8480–90. doi:10.1021/bi992142f. PMID 10913253. 
  16. ^ Edlund T, Jessell TM (Jan 1999). "Progression from extrinsic to intrinsic signaling in cell fate specification: a view from the nervous system". Cell 96 (2): 211–24. doi:10.1016/s0092-8674(00)80561-9. PMID 9988216. 

External links[edit]

Further reading[edit]