Structural basis for activation of the titin kinase domain during myofibrillogenesis

@article{Mayans1998StructuralBF,
  title={Structural basis for activation of the titin kinase domain during myofibrillogenesis},
  author={Olga Mayans and P. van der Ven and Matthias Wilm and Alexander Mues and Paul Young and Dieter O. F{\"u}rst and Matthias Wilmanns and Mathias Gautel},
  journal={Nature},
  year={1998},
  volume={395},
  pages={863-869}
}
The giant muscle protein titin (connectin) is essential in the temporal and spatial control of the assembly of the highly ordered sarcomeres (contractile units) of striated muscle. Here we present the crystal structure of titin's only catalytic domain, an autoregulated serine kinase (titin kinase). The structure shows how the active site is inhibited by a tyrosine of the kinase domain. We describe a dual mechanism of activation of titin kinase that consists of phosphorylation of this tyrosine… 
Cytoskeletal protein kinases: titin and its relations in mechanosensing
  • M. Gautel
  • Biology, Chemistry
    Pflügers Archiv - European Journal of Physiology
  • 2011
TLDR
Titin kinase, the giant elastic ruler protein of striated muscle sarcomeres, contains a catalytic kinase domain related to a family of intrasterically regulated protein kinases, suggesting the MLCK-like kinases have common functions beyond contraction regulation.
Autophosphorylation Is a Mechanism of Inhibition in Twitchin Kinase.
Titin role in muscle homeostasis : the kinase domain
TLDR
It was demonstrated that TK is a catalytically inactive pseudokinase acting as a molecular scaffold and TK and MuRF1 signaling modules are structurally interconnected and genetic perturbation of this link might lead to dilated cardiomyopathy.
The giant protein titin. Emerging roles in physiology and pathophysiology.
Titin is a giant protein of vertebrate striated muscles (M(r), > or = 3000 kD). Its molecules are of filamentous shape and span from the Z disk to the M line, thereby forming a third filament system
The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover
TLDR
A signaling complex where TK interacts with the zinc-finger protein nbr1 through a mechanically inducible conformation is identified where a human mutation in the titin protein kinase domain causes hereditary muscle disease by disrupting this pathway.
Cardiac Hypertrophy and Reduced Contractility in Hearts Deficient in the Titin Kinase Region
TLDR
The titin kinase region emerges as a regulator of contractile function through effects on calcium handling and hypertrophy through protein kinase signal transduction and might provide a rationale for future therapeutic approaches to attenuate or reverse symptoms of heart failure.
Phosphoregulation of the Titin-cap Protein Telethonin in Cardiac Myocytes*
TLDR
Kinase assays used in conjunction with MS and site-directed mutagenesis confirmed telethonin as a substrate for protein kinase D and Ca2+/calmodulin-dependent kinase II in vitro and identified Ser-157 and Ser-161 as the phosphorylation sites.
Mechanoenzymatics of titin kinase
TLDR
It is shown that mechanical strain activates ATP binding before unfolding of the structural titin domains, and that TK can thus act as a biological force sensor and identify the steps in which the autoinhibition of TK is mechanically relieved at low forces, leading to binding of the cosubstrate ATP and priming the enzyme for subsequent autophosphorylation and substrate turnover.
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References

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TLDR
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TLDR
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  • K. Maruyama
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 1997
TLDR
The structure and function of the giant elastic protein connectin/titin are described on the basis of recent investigations and the longitudinal continuity of myosin‐, actin‐free sarcomeres is explained by the linkage of freed connectin filaments extending from both sides of the Z lines in a sarcomere.
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TLDR
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TLDR
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TLDR
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TLDR
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