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Titin kinase is an inactive pseudokinase scaffold that supports MuRF1 recruitment to the sarcomeric M-line.

Bogomolovas J, Gasch A, Simkovic F, Rigden DJ, Labeit S, Mayans O
Open Biol 4 140041 (2014)
Cited: 39 times
EuropePMC logo PMID: 24850911

Abstract

Striated muscle tissues undergo adaptive remodelling in response to mechanical load. This process involves the myofilament titin and, specifically, its kinase domain (TK; titin kinase) that translates mechanical signals into regulatory pathways of gene expression in the myofibril. TK mechanosensing appears mediated by a C-terminal regulatory tail (CRD) that sterically inhibits its active site. Allegedly, stretch-induced unfolding of this tail during muscle function releases TK inhibition and leads to its catalytic activation. However, the cellular pathway of TK is poorly understood and substrates proposed to date remain controversial. TK's best-established substrate is Tcap, a small structural protein of the Z-disc believed to link TK to myofibrillogenesis. Here, we show that TK is a pseudokinase with undetectable levels of catalysis and, therefore, that Tcap is not its substrate. Inactivity is the result of two atypical residues in TK's active site, M34 and E147, that do not appear compatible with canonical kinase patterns. While not mediating stretch-dependent phospho-transfers, TK binds the E3 ubiquitin ligase MuRF1 that promotes sarcomeric ubiquitination in a stress-induced manner. Given previous evidence of MuRF2 interaction, we propose that the cellular role of TK is to act as a conformationally regulated scaffold that functionally couples the ubiquitin ligases MuRF1 and MuRF2, thereby coordinating muscle-specific ubiquitination pathways and myofibril trophicity. Finally, we suggest that an evolutionary dichotomy of kinases/pseudokinases has occurred in TK-like kinases, where invertebrate members are active enzymes but vertebrate counterparts perform their signalling function as pseudokinase scaffolds.

Reviews - 4jnw mentioned but not cited (2)

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Reviews citing this publication (16)

  1. Mechanotransduction in cardiac hypertrophy and failure. Lyon RC, Zanella F, Omens JH, Sheikh F. Circ Res 116 1462-1476 (2015)
  2. The sarcomeric cytoskeleton: from molecules to motion. Gautel M, Djinović-Carugo K. J Exp Biol 219 135-145 (2016)
  3. Mechanical forces during muscle development. Lemke SB, Schnorrer F. Mech Dev 144 92-101 (2017)
  4. YAP-Mediated Mechanotransduction in Skeletal Muscle. Fischer M, Rikeit P, Knaus P, Coirault C. Front Physiol 7 41 (2016)
  5. Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes. Hamdani N, Herwig M, Linke WA. Biophys Rev 9 225-237 (2017)
  6. Pseudokinases: update on their functions and evaluation as new drug targets. Byrne DP, Foulkes DM, Eyers PA. Future Med Chem 9 245-265 (2017)
  7. Thick Filament Protein Network, Functions, and Disease Association. Wang L, Geist J, Grogan A, Hu LR, Kontrogianni-Konstantopoulos A. Compr Physiol 8 631-709 (2018)
  8. Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy. Tabish AM, Azzimato V, Alexiadis A, Buyandelger B, Knöll R. Biophys Rev 9 207-223 (2017)
  9. Cardiac cytoarchitecture - why the "hardware" is important for heart function! Ehler E. Biochim Biophys Acta 1863 1857-1863 (2016)
  10. Mix and (mis-)match - The mechanosensing machinery in the changing environment of the developing, healthy adult and diseased heart. Ward M, Iskratsch T. Biochim Biophys Acta Mol Cell Res 1867 118436 (2020)
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  12. The Work of Titin Protein Folding as a Major Driver in Muscle Contraction. Eckels EC, Tapia-Rojo R, Rivas-Pardo JA, Fernández JM. Annu Rev Physiol 80 327-351 (2018)
  13. Titin (TTN): from molecule to modifications, mechanics, and medical significance. Loescher CM, Hobbach AJ, Linke WA. Cardiovasc Res 118 2903-2918 (2022)
  14. When signalling goes wrong: pathogenic variants in structural and signalling proteins causing cardiomyopathies. Ehsan M, Jiang H, L Thomson K, Gehmlich K. J Muscle Res Cell Motil 38 303-316 (2017)
  15. Advanced Evolution of Pathogenesis Concepts in Cardiomyopathies. Li CJ, Chen CS, Yiang GT, Tsai AP, Liao WT, Wu MY. J Clin Med 8 E520 (2019)
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Articles citing this publication (21)

  1. Titin-based mechanosensing modulates muscle hypertrophy. van der Pijl R, Strom J, Conijn S, Lindqvist J, Labeit S, Granzier H, Ottenheijm C. J Cachexia Sarcopenia Muscle 9 947-961 (2018)
  2. Cardiac myosin light chain is phosphorylated by Ca2+/calmodulin-dependent and -independent kinase activities. Chang AN, Mahajan P, Knapp S, Barton H, Sweeney HL, Kamm KE, Stull JT. Proc Natl Acad Sci U S A 113 E3824-33 (2016)
  3. Hydrogen sulfide regulates muscle RING finger-1 protein S-sulfhydration at Cys44 to prevent cardiac structural damage in diabetic cardiomyopathy. Sun X, Zhao D, Lu F, Peng S, Yu M, Liu N, Sun Y, Du H, Wang B, Chen J, Dong S, Lu F, Zhang W. Br J Pharmacol 177 836-856 (2020)
  4. Binding partners of the kinase domains in Drosophila obscurin and their effect on the structure of the flight muscle. Katzemich A, West RJ, Fukuzawa A, Sweeney ST, Gautel M, Sparrow J, Bullard B. J Cell Sci 128 3386-3397 (2015)
  5. Overexpression of the double homeodomain protein DUX4c interferes with myofibrillogenesis and induces clustering of myonuclei. Vanderplanck C, Tassin A, Ansseau E, Charron S, Wauters A, Lancelot C, Vancutsem K, Laoudj-Chenivesse D, Belayew A, Coppée F. Skelet Muscle 8 2 (2018)
  6. Letter CARP interacts with titin at a unique helical N2A sequence and at the domain Ig81 to form a structured complex. Zhou T, Fleming JR, Franke B, Bogomolovas J, Barsukov I, Rigden DJ, Labeit S, Mayans O. FEBS Lett 590 3098-3110 (2016)
  7. Titin kinase ubiquitination aligns autophagy receptors with mechanical signals in the sarcomere. Bogomolovas J, Fleming JR, Franke B, Manso B, Simon B, Gasch A, Markovic M, Brunner T, Knöll R, Chen J, Labeit S, Scheffner M, Peter C, Mayans O. EMBO Rep 22 e48018 (2021)
  8. DCLK1 autoinhibition and activation in tumorigenesis. Cheng L, Yang Z, Guo W, Wu C, Liang S, Tong A, Cao Z, Thorne RF, Yang SY, Yu Y, Chen Q. Innovation (Camb) 3 100191 (2022)
  9. Twitchin kinase inhibits muscle activity. Matsunaga Y, Hwang H, Franke B, Williams R, Penley M, Qadota H, Yi H, Morran LT, Lu H, Mayans O, Benian GM. Mol Biol Cell 28 1591-1600 (2017)
  10. α-Synemin localizes to the M-band of the sarcomere through interaction with the M10 region of titin. Prudner BC, Roy PS, Damron DS, Russell MA. FEBS Lett 588 4625-4630 (2014)
  11. Twitchin kinase interacts with MAPKAP kinase 2 in Caenorhabditis elegans striated muscle. Matsunaga Y, Qadota H, Furukawa M, Choe HH, Benian GM. Mol Biol Cell 26 2096-2111 (2015)
  12. Exploring Obscurin and SPEG Kinase Biology. Fleming JR, Rani A, Kraft J, Zenker S, Börgeson E, Lange S. J Clin Med 10 984 (2021)
  13. Muscle-specific calpain-3 is phosphorylated in its unique insertion region for enrichment in a myofibril fraction. Ojima K, Ono Y, Hata S, Noguchi S, Nishino I, Sorimachi H. Genes Cells 19 830-841 (2014)
  14. Atypical ALPK2 kinase is not essential for cardiac development and function. Bogomolovas J, Feng W, Yu MD, Huang S, Zhang L, Trexler C, Gu Y, Spinozzi S, Chen J. Am J Physiol Heart Circ Physiol 318 H1509-H1515 (2020)
  15. Conformational changes in twitchin kinase in vivo revealed by FRET imaging of freely moving C. elegans. Porto D, Matsunaga Y, Franke B, Williams RM, Qadota H, Mayans O, Benian GM, Lu H. Elife 10 e66862 (2021)
  16. Why exercise builds muscles: titin mechanosensing controls skeletal muscle growth under load. Ibata N, Terentjev EM. Biophys J 120 3649-3663 (2021)
  17. 'Students-as-partners' scheme enhances postgraduate students' employability skills while addressing gaps in bioinformatics education. Mello LV, Tregilgas L, Cowley G, Gupta A, Makki F, Jhutty A, Shanmugasundram A. High Educ Pedagog 2 43-57 (2017)
  18. Titin M-line insertion sequence 7 is required for proper cardiac function in mice. Biquand A, Spinozzi S, Tonino P, Cosette J, Strom J, Elbeck Z, Knöll R, Granzier H, Lostal W, Richard I. J Cell Sci 134 jcs258684 (2021)
  19. Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere. Agarwal R, Wakimoto H, Paulo JA, Zhang Q, Reichart D, Toepfer C, Sharma A, Tai AC, Lun M, Gorham J, DePalma SR, Gygi SP, Seidman JG, Seidman CE. Circulation 146 1674-1693 (2022)
  20. A PAX6-regulated receptor tyrosine kinase pairs with a pseudokinase to activate immune defense upon oomycete recognition in Caenorhabditis elegans. Drury F, Grover M, Hintze M, Saunders J, Fasseas MK, Constantinou C, Barkoulas M. Proc Natl Acad Sci U S A 120 e2300587120 (2023)
  21. Structural diversity in the atomic resolution 3D fingerprint of the titin M-band segment. Chatziefthimiou SD, Hornburg P, Sauer F, Mueller S, Ugurlar D, Xu ER, Wilmanns M. PLoS One 14 e0226693 (2019)


Related citations provided by authors (2)

  1. Structural basis for activation of the titin kinase domain during myofibrillogenesis.. Mayans O, van der Ven PF, Wilm M, Mues A, Young P, Fürst DO, Wilmanns M, Gautel M Nature 395 863-9 (1998)
  2. X-ray analysis of protein crystals with thin-plate morphology. Mayans O, Wilmanns M J Synchrotron Radiat 6 1016-1020 (1999)

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