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Modulation of cardiac thin filament structure by phosphorylated troponin-I analyzed by protein-protein docking and molecular dynamics simulation.
- Source :
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Archives of Biochemistry & Biophysics . Aug2022, Vol. 725, pN.PAG-N.PAG. 1p. - Publication Year :
- 2022
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Abstract
- 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. [Display omitted] • Cardiac muscle troponin-I contains a phosphorylation-sensitive N-terminal extension. • Phosphorylation of TnI Ser23 and Ser24 increases the rate of cardiac relaxation. • We carried out atomic modeling and ran molecular dynamics on cardiac thin filaments. • PhosphoSer23/24-tropomyosin interaction occurs during molecular dynamics simulation. • Phosphorylation-dependent linkage likely favors tropomyosin off-state switching. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00039861
- Volume :
- 725
- Database :
- Academic Search Index
- Journal :
- Archives of Biochemistry & Biophysics
- Publication Type :
- Academic Journal
- Accession number :
- 157252693
- Full Text :
- https://doi.org/10.1016/j.abb.2022.109282