Energy landscapes reveal the myopathic effects of tropomyosin mutations
[Display omitted] •Interaction energies between mutant tropomyosins and actin were calculated.•Missense mutations reset the switching mechanism controlling muscle contraction.•Mutations distort energy landscapes in ways that explain many phenotypic traits.•Outcomes of mutations can be predicted in s...
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Published in | Archives of biochemistry and biophysics Vol. 564; pp. 89 - 99 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
15.12.2014
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Subjects | |
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Abstract | [Display omitted]
•Interaction energies between mutant tropomyosins and actin were calculated.•Missense mutations reset the switching mechanism controlling muscle contraction.•Mutations distort energy landscapes in ways that explain many phenotypic traits.•Outcomes of mutations can be predicted in silico and validated experimentally.•Post-translational interventions can rescue regulatory imbalances.
Striated muscle contraction is regulated by an interaction network connecting the effects of troponin, Ca2+, and myosin-heads to the azimuthal positioning of tropomyosin along thin filaments. Many missense mutations, located at the actin–tropomyosin interface, however, reset the regulatory switching mechanism either by weakening or strengthening residue-specific interactions, leading to hyper- or hypo-contractile pathologies. Here, we compute energy landscapes for the actin–tropomyosin interface and quantify contributions of single amino acid residues to actin–tropomyosin binding. The method is a useful tool to assess effects of actin and tropomyosin mutations, potentially relating initial stages of myopathy to alterations in thin filament stability and regulation. Landscapes for mutant filaments linked to hyper-contractility provide a simple picture that describes a decrease in actin–tropomyosin interaction energy. Destabilizing the blocked (relaxed)-state parallels previously noted enhanced Ca2+-sensitivity conferred by these mutants. Energy landscapes also identify post-translational modifications that can rescue regulatory imbalances. For example, cardiomyopathy-associated E62Q tropomyosin mutation weakens actin–tropomyosin interaction, but phosphorylation of neighboring S61 rescues the binding-deficit, results confirmed experimentally by in vitro motility assays. Unlike results on hyper-contractility-related mutants, landscapes for tropomyosin mutants tied to hypo-contractility do not present a straightforward picture. These mutations may affect other components of the regulatory network, e.g., troponin–tropomyosin signaling. |
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AbstractList | Striated muscle contraction is regulated by an interaction network connecting the effects of troponin, Ca
2+
, and myosin-heads to the azimuthal positioning of tropomyosin along thin filaments. Many missense mutations, located at the actin-tropomyosin interface, however, reset the regulatory switching mechanism either by weakening or strengthening residue-specific interactions, leading to hyper- or hypo-contractile pathologies. Here, we compute energy landscapes for the actin-tropomyosin interface and quantify contributions of single amino acid residues to actin-tropomyosin binding. The method is a useful tool to assess effects of actin and tropomyosin mutations, potentially relating initial stages of myopathy to alterations in thin filament stability and regulation. Landscapes for mutant filaments linked to hyper-contractility provide a simple picture that describes a decrease in actin-tropomyosin interaction energy. Destabilizing the blocked (relaxed)-state parallels previously noted enhanced Ca
2+
-sensitivity conferred by these mutants. Energy landscapes also identify post-translational modifications that can rescue regulatory imbalances. For example, cardiomyopathy-associated E62Q tropomyosin mutation weakens actin-tropomyosin interaction, but phosphorylation of neighboring S61 rescues the binding-deficit, results confirmed experimentally by
in vitro
motility assays. Unlike results on hyper-contractility-related mutants, landscapes for tropomyosin mutants tied to hypo-contractility do not present a straightforward picture. These mutations may affect other components of the regulatory network, e.g., troponin-tropomyosin signaling. Striated muscle contraction is regulated by an interaction network connecting the effects of troponin, Ca(2+), and myosin-heads to the azimuthal positioning of tropomyosin along thin filaments. Many missense mutations, located at the actin-tropomyosin interface, however, reset the regulatory switching mechanism either by weakening or strengthening residue-specific interactions, leading to hyper- or hypo-contractile pathologies. Here, we compute energy landscapes for the actin-tropomyosin interface and quantify contributions of single amino acid residues to actin-tropomyosin binding. The method is a useful tool to assess effects of actin and tropomyosin mutations, potentially relating initial stages of myopathy to alterations in thin filament stability and regulation. Landscapes for mutant filaments linked to hyper-contractility provide a simple picture that describes a decrease in actin-tropomyosin interaction energy. Destabilizing the blocked (relaxed)-state parallels previously noted enhanced Ca(2+)-sensitivity conferred by these mutants. Energy landscapes also identify post-translational modifications that can rescue regulatory imbalances. For example, cardiomyopathy-associated E62Q tropomyosin mutation weakens actin-tropomyosin interaction, but phosphorylation of neighboring S61 rescues the binding-deficit, results confirmed experimentally by in vitro motility assays. Unlike results on hyper-contractility-related mutants, landscapes for tropomyosin mutants tied to hypo-contractility do not present a straightforward picture. These mutations may affect other components of the regulatory network, e.g., troponin-tropomyosin signaling. [Display omitted] •Interaction energies between mutant tropomyosins and actin were calculated.•Missense mutations reset the switching mechanism controlling muscle contraction.•Mutations distort energy landscapes in ways that explain many phenotypic traits.•Outcomes of mutations can be predicted in silico and validated experimentally.•Post-translational interventions can rescue regulatory imbalances. Striated muscle contraction is regulated by an interaction network connecting the effects of troponin, Ca2+, and myosin-heads to the azimuthal positioning of tropomyosin along thin filaments. Many missense mutations, located at the actin–tropomyosin interface, however, reset the regulatory switching mechanism either by weakening or strengthening residue-specific interactions, leading to hyper- or hypo-contractile pathologies. Here, we compute energy landscapes for the actin–tropomyosin interface and quantify contributions of single amino acid residues to actin–tropomyosin binding. The method is a useful tool to assess effects of actin and tropomyosin mutations, potentially relating initial stages of myopathy to alterations in thin filament stability and regulation. Landscapes for mutant filaments linked to hyper-contractility provide a simple picture that describes a decrease in actin–tropomyosin interaction energy. Destabilizing the blocked (relaxed)-state parallels previously noted enhanced Ca2+-sensitivity conferred by these mutants. Energy landscapes also identify post-translational modifications that can rescue regulatory imbalances. For example, cardiomyopathy-associated E62Q tropomyosin mutation weakens actin–tropomyosin interaction, but phosphorylation of neighboring S61 rescues the binding-deficit, results confirmed experimentally by in vitro motility assays. Unlike results on hyper-contractility-related mutants, landscapes for tropomyosin mutants tied to hypo-contractility do not present a straightforward picture. These mutations may affect other components of the regulatory network, e.g., troponin–tropomyosin signaling. |
Author | Lehman, William Farman, Gerrie P. Orzechowski, Marek Fischer, Stefan Moore, Jeffrey R. |
AuthorAffiliation | b Computational Biochemistry Group, Interdisciplinary Center for Scientific Computing (IWR), University of Heidelberg, Im Neuenheimer Feld 368, Heidelberg D69120, Germany a Department of Physiology & Biophysics, Boston University School of Medicine, 72 East Concord Street, Boston, Massachusetts 02118, USA |
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Author_xml | – sequence: 1 givenname: Marek surname: Orzechowski fullname: Orzechowski, Marek organization: Department of Physiology & Biophysics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA – sequence: 2 givenname: Stefan surname: Fischer fullname: Fischer, Stefan organization: Computational Biochemistry Group, Interdisciplinary Center for Scientific Computing (IWR), University of Heidelberg, Im Neuenheimer Feld 368, Heidelberg D69120, Germany – sequence: 3 givenname: Jeffrey R. surname: Moore fullname: Moore, Jeffrey R. organization: Department of Physiology & Biophysics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA – sequence: 4 givenname: William surname: Lehman fullname: Lehman, William email: wlehman@bu.edu organization: Department of Physiology & Biophysics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA – sequence: 5 givenname: Gerrie P. surname: Farman fullname: Farman, Gerrie P. organization: Department of Physiology & Biophysics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA |
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Keywords | Muscle regulation Actin Tropomyosin Cardiomyopathy Myosin |
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•Interaction energies between mutant tropomyosins and actin were calculated.•Missense mutations reset the switching mechanism controlling... Striated muscle contraction is regulated by an interaction network connecting the effects of troponin, Ca(2+), and myosin-heads to the azimuthal positioning of... Striated muscle contraction is regulated by an interaction network connecting the effects of troponin, Ca 2+ , and myosin-heads to the azimuthal positioning of... |
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SubjectTerms | Actin Actin Cytoskeleton - chemistry Actin Cytoskeleton - genetics Actin Cytoskeleton - metabolism Amino Acid Substitution Calcium - chemistry Calcium - metabolism Cardiomyopathies Cardiomyopathy Genetic Diseases, Inborn Humans Muscle regulation Mutation, Missense Myosin Signal Transduction - genetics Tropomyosin Tropomyosin - chemistry Tropomyosin - genetics Tropomyosin - metabolism |
Title | Energy landscapes reveal the myopathic effects of tropomyosin mutations |
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