ArticleThe Journal of biological chemistry2013
Conserved Asp-137 is important for both structure and regulatory functions of cardiac α-tropomyosin (α-TM) in a novel transgenic mouse model expressing α-TM-D137L.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 24 citations in OpenAlex.
- Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling.Quarterly reviews of biophysics · 2023Review
- Computational and biophysical determination of pathogenicity of variants of unknown significance in cardiac thin filament.JCI insight · 2021Article
- Functional outcomes of structural peculiarities of striated muscle tropomyosin.Journal of muscle research and cell motility · 2020Review
- A new twist on tropomyosin binding to actin filaments: perspectives on thin filament function, assembly and biomechanics.Journal of muscle research and cell motility · 2020Review
- Article
- Precise Binding of Tropomyosin on Actin Involves Sequence-Dependent Variance in Coiled-Coil Twisting.Biophysical journal · 2018Article
- Calcium in Brugada Syndrome: Questions for Future Research.Frontiers in physiology · 2018Review
- Clinically Divergent Mutation Effects on the Structure and Function of the Human Cardiac Tropomyosin Overlap.Biochemistry · 2017Article
- The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy.Journal of molecular and cellular cardiology · 2017Article
- Overview of the Muscle Cytoskeleton.Comprehensive Physiology · 2017Review
- The Relaxation Properties of Myofibrils Are Compromised by Amino Acids that Stabilize α-Tropomyosin.Biophysical journal · 2017Article
- Investigating the effects of tropomyosin mutations on its flexibility and interactions with filamentous actin using molecular dynamics simulation.Journal of muscle research and cell motility · 2016Article
- Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies.The Journal of biological chemistry · 2015Article
- Pathogenesis associated with a restrictive cardiomyopathy mutant in cardiac troponin T is due to reduced protein stability and greatly increased myofilament Ca2+ sensitivity.Biochimica et biophysica acta · 2015Article
- Deficiency of cardiomyocyte-specific microRNA-378 contributes to the development of cardiac fibrosis involving a transforming growth factor β (TGFβ1)-dependent paracrine mechanism.The Journal of biological chemistry · 2014Article
- Allosteric effects of cardiac troponin TNT1 mutations on actomyosin binding: a novel pathogenic mechanism for hypertrophic cardiomyopathy.Archives of biochemistry and biophysics · 2014Article
- Maladaptive modifications in myofilament proteins and triggers in the progression to heart failure and sudden death.Pflugers Archiv : European journal of physiology · 2014Review
- Instability in the central region of tropomyosin modulates the function of its overlapping ends.Biophysical journal · 2013Article
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11 authors at 2 institutions in 1 country.
Funding
Abstract
α-Tropomyosin (α-TM) has a conserved, charged Asp-137 residue located in the hydrophobic core of its coiled-coil structure, which is unusual in that the residue is found at a position typically occupied by a hydrophobic residue. Asp-137 is thought to destabilize the coiled-coil and so impart structural flexibility to the molecule, which is believed to be crucial for its function in the heart. A previous in vitro study indicated that the conversion of Asp-137 to a more typical canonical Leu alters flexibility of TM and affects its in vitro regulatory functions. However, the physiological importance of the residue Asp-137 and altered TM flexibility is unknown. In this study, we further analyzed structural properties of the α-TM-D137L variant and addressed the physiological importance of TM flexibility in cardiac function in studies with a novel transgenic mouse model expressing α-TM-D137L in the heart. Our NMR spectroscopy data indicated that the presence of D137L introduced long range rearrangements in TM structure. Differential scanning calorimetry measurements demonstrated that α-TM-D137L has higher thermal stability compared with α-TM, which correlated with decreased flexibility. Hearts of transgenic mice expressing α-TM-D137L showed systolic and diastolic dysfunction with decreased myofilament Ca(2+) sensitivity and cardiomyocyte contractility without changes in intracellular Ca(2+) transients or post-translational modifications of major myofilament proteins. We conclude that conversion of the highly conserved Asp-137 to Leu results in loss of flexibility of TM that is important for its regulatory functions in mouse hearts. Thus, our results provide insight into the link between flexibility of TM and its function in ejecting hearts.
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