Titin(S) : Towards an Atomic Understanding of Mechanosensory Events in the Elastic Scaffolds of the Muscle Sarcomere

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The giant intra-sarcomeric filaments of the titin-like family are key orchestrators of stretch-sensing pathways that regulate muscle responses to mechanical load. Despite acute variations in the length and domain organization of these filamentous proteins across the animal biodiversity, they all comprise numerous Ig/FnIII domains linked in series and one or two kinase domains invariably located near their C-terminus. Combining the 3D-structural elucidation of multi-domain components at atomic level, in silico simulations, molecular engineering and in vivo transgenic muscle technologies, we are revealing the molecular events taking place during mechanosensing in titin-like proteins. Our findings show that the sensory role of titin is enabled by a subtle interdomain order in the chain, imposed by short linkers that sterically govern domain packing and dynamics. This modular design is sensitive to mechanical deformations but affords a ‘‘chain memory’’ mechanism for molecular recovery. The local disruption of such domain arrangements by genetic mutation leads to human myopathy. Our data show that also the kinase domains of titin-like proteins undergo elastic deformations in their regulatory, flanking segments during muscle activity in vivo. Contrary to expectations, these kinases are catalyticallydispensable for muscle function and development. Instead, they act as regulated scaffolds for the recruitment of turnover/signaling proteins onto kinase-based signalosomes. This talk will provide a molecular perspective on the stretchinduced mechanics and signaling of titin-like proteins.

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ISO 690MAYANS, Olga, Jennifer R. FLEMING, Rhys WILLIAMS, Barbara FRANKE, Hang LU, Guy BERRIAN, 2016. Titin(S) : Towards an Atomic Understanding of Mechanosensory Events in the Elastic Scaffolds of the Muscle Sarcomere. In: Biophysical Journal. 2016, 110(3), 185a. ISSN 0006-3495. eISSN 1542-0086. Available under: doi: 10.1016/j.bpj.2015.11.1031
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@article{Mayans2016-02Titin-34531,
  year={2016},
  doi={10.1016/j.bpj.2015.11.1031},
  title={Titin(S) : Towards an Atomic Understanding of Mechanosensory Events in the Elastic Scaffolds of the Muscle Sarcomere},
  number={3},
  volume={110},
  issn={0006-3495},
  journal={Biophysical Journal},
  author={Mayans, Olga and Fleming, Jennifer R. and Williams, Rhys and Franke, Barbara and Lu, Hang and Berrian, Guy},
  note={Article Number: 185a}
}
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    <dcterms:abstract>The giant intra-sarcomeric filaments of the titin-like family are key orchestrators&#xD;
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load. Despite acute variations in the length and domain organization of these&#xD;
filamentous proteins across the animal biodiversity, they all comprise numerous&#xD;
Ig/FnIII domains linked in series and one or two kinase domains invariably&#xD;
located near their C-terminus. Combining the 3D-structural elucidation of&#xD;
multi-domain components at atomic level, in silico simulations, molecular engineering&#xD;
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events taking place during mechanosensing in titin-like proteins.&#xD;
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but affords a ‘‘chain memory’’ mechanism for molecular recovery. The&#xD;
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undergo elastic deformations in their regulatory, flanking segments during muscle&#xD;
activity in vivo. Contrary to expectations, these kinases are catalyticallydispensable&#xD;
for muscle function and development. Instead, they act as regulated&#xD;
scaffolds for the recruitment of turnover/signaling proteins onto kinase-based&#xD;
signalosomes. This talk will provide a molecular perspective on the stretchinduced&#xD;
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