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

Zsolt Mártonfalvi, Pasquale Bianco, Marco Linari, Marco Caremani, Attila Nagy, Vincenzo Lombardi, Miklós Kellermayer

Research output: Contribution to journalArticle

17 Citations (Scopus)

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, stepwise 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. Highresolution 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, which, by dynamically exposing ligand-binding sites, could set the stage for the biochemical sensing of the mechanical status of the sarcomere.

Original languageEnglish
Pages (from-to)858-870
Number of pages13
JournalJournal of cell science
Volume127
Issue number4
DOIs
Publication statusPublished - Feb 15 2014

Keywords

  • Atomic force microscopy
  • Mechanosensor
  • Monte-Carlo simulation
  • Optical tweezers
  • PEVK domain
  • Single-molecule mechanics
  • Titin

ASJC Scopus subject areas

  • Cell Biology

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