Cardiac troponin T N-domain variant destabilizes the actin interface resulting in disturbed myofilament function

Maicon Landim-Vieira, Weikang Ma, Taejeong Song, Hosna Rastegarpouyani, Henry Gong, Isabella Leite Coscarella, Sylvia J.P. Bogaards, Stefan P. Conijn, Coen A.C. Ottenheijm, Hyun S. Hwang, Maria Papadaki, Bjorn C. Knollmann, Sakthivel Sadayappan, Thomas C. Irving, Vitold E. Galkin, P. Bryant Chase, Jose Renato Pinto

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Missense variant Ile79Asn in human cardiac troponin T (cTnT-I79N) has been associated with hypertrophic cardiomyopathy and sudden cardiac arrest in juveniles. cTnT-I79N is located in the cTnT N-terminal (TnT1) loop region and is known for its pathological and prognostic relevance. A recent structural study revealed that I79 is part of a hydrophobic interface between the TnT1 loop and actin, which stabilizes the relaxed (OFF) state of the cardiac thin filament. Given the importance of understanding the role of TnT1 loop region in Ca2+ regulation of the cardiac thin filament along with the underlying mechanisms of cTnT-I79N-linked pathogenesis, we investigated the effects of cTnT-I79N on cardiac myofilament function. Transgenic I79N (Tg-I79N) muscle bundles displayed increased myofilament Ca2+ sensitivity, smaller myofilament lattice spacing, and slower crossbridge kinetics. These findings can be attributed to destabilization of the cardiac thin filament's relaxed state resulting in an increased number of crossbridges during Ca2+ activation. Additionally, in the low Ca2+-relaxed state (pCa8), we showed that more myosin heads are in the disordered-relaxed state (DRX) that are more likely to interact with actin in cTnT-I79N muscle bundles. Dysregulation of the myosin super-relaxed state (SRX) and the SRX/DRX equilibrium in cTnT-I79N muscle bundles likely result in increased mobility of myosin heads at pCa8, enhanced actomyosin interactions as evidenced by increased active force at low Ca2+, and increased sinusoidal stiffness. These findings point to a mechanism whereby cTnT-I79N weakens the interaction of the TnT1 loop with the actin filament, which in turn destabilizes the relaxed state of the cardiac thin filament.

Original languageEnglish (US)
Article numbere2221244120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number23
DOIs
StatePublished - Jun 2023
Externally publishedYes

Keywords

  • TnT1 loop region
  • cardiac thin filament
  • cardiac troponin T tail domain
  • cardiomyopathy
  • myosin SRX/DRX

ASJC Scopus subject areas

  • General

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