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• W2912678546 abstract "Mutations in cardiac troponin T (cTnT), a component of the cardiac thin filament (cTF), are known to cause changes in protein structure and dynamics leading to pathological cardiac remodeling observed in patients with hypertrophic (HCM) and dilated (DCM) cardiomyopathies. In this complex system, mutations in cTnT separated by only a few amino acids can cause divergent cardiomyopathies, highlighting the importance of primary structural and dynamic “triggers” that lead to disease. To begin to correlate genotype to phenotype, we investigated three cardiomyopathy-linked mutations in the cTnT linker region: DCM-associated mutations R173W and R173Q, and HCM-associated mutation Δ160E. We coupled computational predictions with in-vitro biophysical measurementsto better understand the divergent disease mechanisms. We hypothesize that R173Q/W and Δ160E cause differential structural changes in the cTF linker domain leading to atomic and molecular level changes that initiate pathogenic remodeling. Differential scanning calorimetry on all 3 mutations showed an increased thermal stability required to unfold the Tm:Tn complex from actin, suggesting altered protein interactions. To obtain further resolution, molecular dynamics (MD) simulations and time-resolved fluorescence resonance energy transfer (TR-FRET) studies were employed. Previous studies showed that Δ160E caused a decreased distance between the linker region of cTnT and the tropomyosin C-terminus, resulting in decreased linker flexibility. In contrast, MD simulations of the TF containing R173W/Q show an increase distance between the linker region of cTnT and the C-terminus of tropomyosin and actin 374. Further clarification of these data will be provided by ongoing TR-FRET studies to confirm structural distance changes in the liker region in fully reconstituted cTF. This iterative process will allow us to build predictive tools to test cTF mutations associated with these cardiomyopathies and eventually to design and implement more precise therapeutic interventions." @default.
• W2912678546 created "2019-02-21" @default.
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• W2912678546 date "2019-02-01" @default.
• W2912678546 modified "2023-09-26" @default.
• W2912678546 title "Computational and Experimental Investigation of Cardiac Troponin T R173Q, R173W and Δ160E Mutation Specific Correlates to Disease" @default.
• W2912678546 doi "https://doi.org/10.1016/j.bpj.2018.11.1438" @default.
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