What does this research mean for the field?

Dilated cardiomyopathy-associated mutations and cTnI phosphomimetic mutants destabilize the active orientation of the regulatory N-terminal domain of cardiac troponin C (cNTnC), reducing its 15N R2 relaxation rate and shifting the complex toward a dormant orientation. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

April 24, 2021Journal of Molecular BiologyOpen Access

Dilated Cardiomyopathy Mutations and Phosphorylation disrupt the Active Orientation of Cardiac Troponin C

Q: What is the clinical evidence from this study?

Study design: Other. Population: Dilated Cardiomyopathy. Intervention: cTnI phosphomimetic and DCM-associated mutations vs. Wild-type cTn complex. Primary outcome: 15N R2 relaxation rate of cNTnC.

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Key result

Dilated cardiomyopathy-associated mutations and cTnI phosphomimetic mutants destabilized the active orientation of cNTnC, reducing its 15N R2 relaxation rate from 30 to 17-23 s-1.

Population

Cardiac troponin complex subunits and mutants

Comparison

DCM mutations and phosphomimetics vs unmodified cardiac troponin subunits

Design

In vitro structural biophysical and solution NMR relaxation study

Authors

ZMZabed MahmudUniversity of Alberta PDPrabhpaul S. Dhami CRCaleb Rans

Discussion

Member takes

Implication

Supports troponin equilibrium as DCM mechanism; hypothesis-generating for targeted therapies, needs in vivo validation.

Structured PICO

Population

Cardiac troponin complex (cTnC, cTnI, cTnT) and its regulatory N-terminal domain (cNTnC)

Intervention

cTnI phosphomimetic mutants (S22D/S23D, S41D/S43D) and dilated cardiomyopathy-associated mutations (cTnI K35Q, cTnC D75Y, cTnC G159D)

Comparator

Wild-type/unmodified cardiac troponin complex

Outcome

Orientation and tumbling dynamics of cNTnC measured by solution NMR 15N R2 relaxation analysissurrogate

Dilated cardiomyopathy mutations and phosphorylation destabilize the active orientation of cardiac troponin C, indicating that calcium sensitivity is regulated by an equilibrium between active and dormant structural states.

Cite This Study

Mahmud et al. (2021) studied Dilated Cardiomyopathy. cTnI phosphomimetic and DCM-associated mutations vs. Wild-type cTn complex was evaluated on 15N R2 relaxation rate of cNTnC. Dilated cardiomyopathy-associated mutations and cTnI phosphomimetic mutants destabilized the active orientation of cNTnC, reducing its 15N R2 relaxation rate from 30 to 17-23 s-1.

synapsesocial.com/papers/6a1c0bf74ebd09f3dfa96002 https://doi.org/10.1016/j.jmb.2021.167010

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April 24, 2021Journal of Molecular BiologyOpen Access

Dilated Cardiomyopathy Mutations and Phosphorylation disrupt the Active Orientation of Cardiac Troponin C

View Full Paper

Ask AI

Bookmark

Key result

Dilated cardiomyopathy-associated mutations and cTnI phosphomimetic mutants destabilized the active orientation of cNTnC, reducing its 15N R2 relaxation rate from 30 to 17-23 s-1.

Population

Cardiac troponin complex subunits and mutants

Comparison

DCM mutations and phosphomimetics vs unmodified cardiac troponin subunits

Design

In vitro structural biophysical and solution NMR relaxation study

Authors

ZMZabed MahmudUniversity of Alberta PDPrabhpaul S. Dhami CRCaleb Rans

Discussion

Member takes

Implication

Supports troponin equilibrium as DCM mechanism; hypothesis-generating for targeted therapies, needs in vivo validation.

Structured PICO

Population

Cardiac troponin complex (cTnC, cTnI, cTnT) and its regulatory N-terminal domain (cNTnC)

Intervention

cTnI phosphomimetic mutants (S22D/S23D, S41D/S43D) and dilated cardiomyopathy-associated mutations (cTnI K35Q, cTnC D75Y, cTnC G159D)

Comparator

Wild-type/unmodified cardiac troponin complex

Outcome

Orientation and tumbling dynamics of cNTnC measured by solution NMR 15N R2 relaxation analysissurrogate

Cite This Study

synapsesocial.com/papers/6a1c0bf74ebd09f3dfa96002 https://doi.org/10.1016/j.jmb.2021.167010

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