Mechanochemical evolution of the giant muscle protein titin as inferred from resurrected proteins

@article{Manteca2017MechanochemicalEO,
  title={Mechanochemical evolution of the giant muscle protein titin as inferred from resurrected proteins},
  author={Aitor Manteca and J{\"o}rg Sch{\"o}nfelder and {\'A}lvaro Alonso-Caballero and Marie J Fertin and Nerea Barruetabe{\~n}a and Bruna F Faria and El{\'i}as Herrero-Gal{\'a}n and Jorge Alegre-Cebollada and David de Sancho and Raul Perez-Jimenez},
  journal={Nature Structural \&Molecular Biology},
  year={2017},
  volume={24},
  pages={652-657}
}
The sarcomere-based structure of muscles is conserved among vertebrates; however, vertebrate muscle physiology is extremely diverse. A molecular explanation for this diversity and its evolution has not been proposed. We use phylogenetic analyses and single-molecule force spectroscopy (smFS) to investigate the mechanochemical evolution of titin, a giant protein responsible for the elasticity of muscle filaments. We resurrect eight-domain fragments of titin corresponding to the common ancestors… 
Evolution of the Highly Repetitive PEVK Region of Titin Across Mammals
TLDR
A bioinformatics tool to annotate PEVK exons from genomic sequences of titin and applied to a diverse set of mammals finds that the very complexity that makes titin a challenge for annotation tools may also promote evolutionary adaptation.
Mechanochemical Evolution of Disulfide Bonds in Proteins.
TLDR
A detailed protocol to study the mechanochemical evolution of proteins using a fragment of the giant muscle protein titin as example and can be easily adapted to AFS studies of any resurrected mechanical force bearing protein of interest.
The Mechanical Power of Protein Folding
TLDR
The results demonstrate, for the first time, the functional significance of disulfide bonds as potent power amplifiers in titin and provide evidence that protein folding can generate substantial amounts of power to supplement the myosin motors during a contraction.
Disulfide isomerization reactions in titin immunoglobulin domains enable a mode of protein elasticity
TLDR
It is shown that disulfide isomerization reactions within Ig domains enable a third mechanism of titin elasticity, and it is proposed that imbalance of the redox status of myocytes can have immediate consequences for the mechanical properties of the sarcomere via alterations of the oxidation state of Titin domains.
Conserved cysteines in titin sustain the mechanical function of cardiomyocytes
TLDR
The regulatory role of conserved, mechanically active titin cysteines is reported to be reversibly oxidized in basal conditions leading to isoform- and force-dependent modulation of titin stiffness and dynamics.
The power of the force: mechano-physiology of the giant titin.
TLDR
Titin - the largest protein in the human body - spans half of the muscle sarcomere from the Z-disk to the M-band through a single polypeptide chain, considered the third filament of muscle, after the thick-myosin and the thin-actin filaments.
Disulfide bonds: the power switches of elastic proteins
TLDR
The results demonstrate, for the first time, the functional significance of disulfide bonds as potent power amplifiers in proteins operating under force.
Structural diversity in the atomic resolution 3D fingerprint of the titin M-band segment
TLDR
The data allow to structurally interpreting distinct pathological readouts that result from titinopathy-associated variants and support general principles that could be used to identify individual structural/functional profiles of hundreds of identically folded protein domains within the sarcomere and other densely crowded cellular environments.
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References

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TLDR
The architecture of sequences in the A band region of titin suggests why thick filament structure is conserved among vertebrates and compares two elements that correlate with tissue stiffness that suggest that titin may act as two springs in series.
The evolution of titin and related giant muscle proteins
TLDR
From a comparison of the kinase domains, titin is predicted to have appeared first during the evolution of the family, followed by twitchin and with the vertebrate MLCKs last to appear.
Hidden complexity in the mechanical properties of titin
TLDR
It is shown that, under physiological forces, the partly unfolded intermediate does not contribute to mechanical strength, and a unified forced unfolding model of all I27 analogues studied is proposed, which concludes that I27 can withstand higher forces in muscle than was predicted previously.
Reverse engineering of the giant muscle protein titin
TLDR
This work uses protein engineering and single-molecule atomic force microscopy to examine the mechanical components that form the elastic region of human cardiac titin and shows the functional reconstitution of a protein from the sum of its parts.
Elasticity and unfolding of single molecules of the giant muscle protein titin
TLDR
Mechanical experiments on single molecules of titin are done to determine their visco-elastic properties, showing that there are two main sources of elasticity: one deriving from the entropy of straightening the molecule; the other consistent with extension of the polypeptide chain in the PEVK region.
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TLDR
It is shown how low-porosity polyacrylamide-gel electrophoresis, optimised for resolving megadalton proteins, can identify differences in titin-isoform expression in the hearts of 10 different vertebrate species and in several skeletal muscles of the rabbit.
Molecular Mechanics of Cardiac Titin's PEVK and N2B Spring Elements*
TLDR
This work characterized the single molecule force-extension curves of the PEVK and N2B-Us spring elements, which together are responsible for physiological levels of passive force in moderately to highly stretched myocardium and calculated the extension of the various spring elements and the forces generated by titin, both as a function of sarcomere length.
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TLDR
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Folding-unfolding transitions in single titin molecules characterized with laser tweezers.
TLDR
Scaling the molecular data up to sarcomeric dimensions reproduced many features of the passive force versus extension curve of muscle fibers, including force hysteresis arises from a difference between the unfolding and refolding kinetics of the molecule relative to the stretch and release rates in the experiments.
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