Low-force transitions in single titin molecules reflect a memory of contractile history

Journal of Cell Science
Zsolt MártonfalviMiklós S Z Kellermayer

Abstract

Titin is a giant elastomeric muscle protein that has been suggested to function as a sensor of sarcomeric stress and strain, but the mechanisms by which it does so are unresolved. To gain insight into its mechanosensory function we manipulated single titin molecules with high-resolution optical tweezers. Discrete, step-wise transitions, with rates faster than canonical Ig domain unfolding occurred during stretch at forces as low as 5 pN. Multiple mechanisms and molecular regions (PEVK, proximal tandem-Ig, N2A) are likely to be involved. The pattern of transitions is sensitive to the history of contractile events. Monte-Carlo simulations of our experimental results predicted that structural transitions begin before the complete extension of the PEVK domain. High-resolution atomic force microscopy (AFM) supported this prediction. Addition of glutamate-rich PEVK domain fragments competitively inhibited the viscoelastic response in both single titin molecules and muscle fibers, indicating that PEVK domain interactions contribute significantly to sarcomere mechanics. Thus, under non-equilibrium conditions across the physiological force range, titin extends by a complex pattern of history-dependent discrete conformational transitions...Continue Reading

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Citations

Jul 23, 2015·Biophysical Journal·Pasquale BiancoMiklós Kellermayer
Jan 23, 2017·Biophysical Journal·Csaba I PongorMiklós Kellermayer
Jun 9, 2016·PLoS Computational Biology·Gudrun Schappacher-TilpWalter Herzog
Jan 18, 2017·Protein Science : a Publication of the Protein Society·Zsolt MártonfalviMiklós Kellermayer
Sep 25, 2017·The Journal of Experimental Biology·Anthony L Hessel, Kiisa C Nishikawa
May 10, 2019·Journal of Applied Physiology·Martin Lakie, Kenneth S Campbell
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Sep 16, 2020·Proceedings of the National Academy of Sciences of the United States of America·Christine M LoescherWolfgang A Linke
Apr 30, 2020·Nature Communications·Jaime Andrés Rivas-PardoJorge Alegre-Cebollada
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Dec 21, 2018·Emerging Topics in Life Sciences·Jaime Andrés Rivas-Pardo
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Sep 4, 2020·Journal of Applied Physiology·Martin Eric HérouxRobert D Herbert
Jul 27, 2021·EMBO Reports·Jörg HöhfeldBettina Warscheid
Aug 18, 2021·Journal of Cell Science·Ariane BiquandIsabelle Richard

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