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… 
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361 Citations
Highly Influential Citations
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361 Citations

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  • 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.
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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.
Structural evidence for a possible role of reversible disulphide bridge formation in the elasticity of the muscle protein titin.
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.
Titin and its associated proteins: the third myofilament system of the sarcomere.
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References

SHOWING 1-10 OF 44 REFERENCES
A calmodulin-binding sequence in the C-terminus of human cardiac titin kinase.
TLDR
Biochemical data indicate that titin kinase as well as peptides from its C-terminus bind to calmodulin in an equimolar complex in the presence of calcium, and it is proposed that this cal modulin-binding region of titin could play a regulatory role for the enzyme, the substrate of which still remains to be identified.
Ca2+ /S100 regulation of giant protein kinases
TLDR
A Ca2+-effector mechanism for protein kinase activation is reported by demonstrating the specific and > 1,000-fold activation of the myosin-associated giantprotein kinase twitchin by Ca2-/S100Al2.
Connectin/titin, giant elastic protein of muscle
  • 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.
Giant protein kinases: domain interactions and structural basis of autoregulation.
TLDR
Together, the structures reveal the cooperative interactions between the autoregulatory region and the residues from the catalytic domain involved in protein substrate binding, ATP binding, catalysis and the activation loop, and explain the differences between the observed autoinhibitory mechanism and the one found in the structure of calmodulin‐dependent kinase I.
Structural Basis for the Autoinhibition of Calcium/Calmodulin-Dependent Protein Kinase I
The structural basis for substrate recognition and control by protein kinases 1
Autophosphorylation of molluscan twitchin and interaction of its kinase domain with calcium/calmodulin.
TLDR
The potential regulation of twitchin by calcium/calmodulin indicates that titin-like molecules may serve dynamic functions during contraction-relaxation cycles in muscle in addition to their functions as cytoskeletal proteins.
The structure of the sarcomeric M band: localization of defined domains of myomesin, M-protein, and the 250-kD carboxy-terminal region of titin by immunoelectron microscopy
TLDR
A panel of 16 polyclonal and monoclonal antibodies directed against unique epitopes of defined sequence was assembled, and immunoelectron microscopy was used to locate the position of the epitopes at the sarcomere level, allowing the localization and orientation of defined domains of titin, myomesin, and M-protein at high resolution.
Two immunoglobulin‐like domains of the Z‐disc portion of titin interact in a conformation‐dependent way with telethonin
Characterization of Substrate Phosphorylation and Use of Calmodulin Mutants to Address Implications from the Enzyme Crystal Structure of Calmodulin-dependent Protein Kinase I*
TLDR
The activation of the enzyme by CaM mutants with substitutions at hydrophobic residues is characterized and the critical role of the N-terminal domain of CaM in regulating the access of ATP to CaMKI is demonstrated.
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