Correlation Engine 2.0
Clear Search sequence regions

  • actins (4)
  • calcium (2)
  • filament (6)
  • myosin (1)
  • peptides (2)
  • regulates (1)
  • skeletal muscle (1)
  • TnC (5)
  • TnI (9)
  • tropomyosin (7)
  • troponin (3)
  • Sizes of these terms reflect their relevance to your search.

    Tropomyosin, controlled by troponin-linked Ca2+-binding, regulates muscle contraction by a macromolecular scale steric-mechanism that governs myosin-crossbridge-actin interactions. At low-Ca2+, C-terminal domains of troponin-I (TnI) trap tropomyosin in a position on thin filaments that interferes with myosin-binding, thus causing muscle relaxation. Steric inhibition is reversed at high-Ca2+ when TnI releases from F-actin-tropomyosin as Ca2+ and the TnI switch-peptide bind to the N-lobe of troponin-C (TnC). The opposite end of cardiac TnI contains a phosphorylation-sensitive ∼30 residue-long N-terminal peptide that is absent in skeletal muscle, and likely modifies these interactions in hearts. Here, PKA-dependent phosphorylation of serine 23 and 24 modulates Ca2+ and possibly switch-peptide binding to TnC, causing faster relaxation during the cardiac-cycle (lusitropy). The cardiac-specific N-terminal TnI domain is not captured in crystal structures of troponin or in cryo-EM reconstructions of thin filaments; thus, its global impact on thin filament structure and function is uncertain. Here, we used protein-protein docking and molecular dynamics simulation-based protocols to build a troponin model that was guided by and hence consistent with the recent seminal Yamada structure of Ca2+-activated thin filaments. We find that when present on thin filaments, phosphorylated Ser23/24 along with adjacent polar TnI residues interact closely with both tropomyosin and the N-lobe of TnC during our simulations. These interactions would likely bias tropomyosin to an off-state positioning on actin. In situ, such enhanced relaxation kinetics would promote cardiac lusitropy. Copyright © 2022 Elsevier Inc. All rights reserved.


    Elumalai Pavadai, Michael J Rynkiewicz, Zeyu Yang, Ian R Gould, Steven B Marston, William Lehman. Modulation of cardiac thin filament structure by phosphorylated troponin-I analyzed by protein-protein docking and molecular dynamics simulation. Archives of biochemistry and biophysics. 2022 Aug 15;725:109282

    Expand section icon Mesh Tags

    Expand section icon Substances

    PMID: 35577070

    View Full Text