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Nature Reviews. Cardiology Jun 2022Variants in >12 genes encoding sarcomeric proteins can cause various cardiomyopathies. The two most common are hypertrophic cardiomyopathy (HCM) and dilated... (Review)
Review
Variants in >12 genes encoding sarcomeric proteins can cause various cardiomyopathies. The two most common are hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Current therapeutics do not target the root causes of these diseases, but attempt to prevent disease progression and/or to manage symptoms. Accordingly, novel approaches are being developed to treat the cardiac muscle dysfunction directly. Challenges to developing therapeutics for these diseases include the diverse mechanisms of pathogenesis, some of which are still being debated and defined. Four small molecules that modulate the myosin motor protein in the cardiac sarcomere have shown great promise in the settings of HCM and DCM, regardless of the underlying genetic pathogenesis, and similar approaches are being developed to target other components of the sarcomere. In the setting of HCM, mavacamten and aficamten bind to the myosin motor and decrease the ATPase activity of myosin. In the setting of DCM, omecamtiv mecarbil and danicamtiv increase myosin activity in cardiac muscle (but omecamtiv mecarbil decreases myosin activity in vitro). In this Review, we discuss the therapeutic strategies to alter sarcomere contractile activity and summarize the data indicating that targeting one protein in the sarcomere can be effective in treating patients with genetic variants in other sarcomeric proteins, as well as in patients with non-sarcomere-based disease.
Topics: Cardiomyopathies; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Humans; Mutation; Myocardium; Myosins; Sarcomeres
PubMed: 35304599
DOI: 10.1038/s41569-022-00682-0 -
International Journal of Molecular... Sep 2018Actin-myosin interactions play crucial roles in the generation of cellular force and movement. The molecular mechanism involves structural transitions at the interface... (Review)
Review
Actin-myosin interactions play crucial roles in the generation of cellular force and movement. The molecular mechanism involves structural transitions at the interface between actin and myosin's catalytic domain, and within myosin's light chain domain, which contains binding sites for essential (ELC) and regulatory light chains (RLC). High-resolution crystal structures of isolated actin and myosin, along with cryo-electron micrographs of actin-myosin complexes, have been used to construct detailed structural models for actin-myosin interactions. However, these methods are limited by disorder, particularly within the light chain domain, and they do not capture the dynamics within this complex under physiological conditions in solution. Here we highlight the contributions of site-directed fluorescent probes and time-resolved fluorescence resonance energy transfer (TR-FRET) in understanding the structural dynamics of the actin-myosin complex in solution. A donor fluorescent probe on actin and an acceptor fluorescent probe on myosin, together with high performance TR-FRET, directly resolves structural states in the bound actin-myosin complex during its interaction with adenosine triphosphate (ATP). Results from these studies have profound implications for understanding the contractile function of actomyosin and establish the feasibility for the discovery of allosteric modulators of the actin-myosin interaction, with the ultimate goal of developing therapies for muscle disorders.
Topics: Actins; Adenosine Triphosphate; Animals; Disease Susceptibility; Drug Discovery; Humans; Muscle, Skeletal; Mutation; Myocardium; Myosin Light Chains; Myosins; Protein Binding; Protein Isoforms; Structure-Activity Relationship
PubMed: 30189615
DOI: 10.3390/ijms19092628 -
Advances in Experimental Medicine and... 2020Directed movements on actin filaments within the cell are powered by molecular motors of the myosin superfamily. On actin filaments, myosin motors convert the energy... (Review)
Review
Directed movements on actin filaments within the cell are powered by molecular motors of the myosin superfamily. On actin filaments, myosin motors convert the energy from ATP into force and movement. Myosin motors power such diverse cellular functions as cytokinesis, membrane trafficking, organelle movements, and cellular migration. Myosin generates force and movement via a number of structural changes associated with hydrolysis of ATP, binding to actin, and release of the ATP hydrolysis products while bound to actin. Herein we provide an overview of those structural changes and how they relate to the actin-myosin ATPase cycle. These structural changes are the basis of chemo-mechanical transduction by myosin motors.
Topics: Actin Cytoskeleton; Actins; Adenosine Triphosphate; Hydrolysis; Movement; Myosins
PubMed: 32451853
DOI: 10.1007/978-3-030-38062-5_2 -
Advances in Experimental Medicine and... 2020Class XVIII myosins represent a branch of the myosin family tree characterized by the presence of large N- and C-terminal extensions flanking a generic myosin core.... (Review)
Review
Class XVIII myosins represent a branch of the myosin family tree characterized by the presence of large N- and C-terminal extensions flanking a generic myosin core. These myosins display the highest sequence similarity to conventional class II muscle myosins and are compatible with but not restricted to myosin-2 contractile structures. Instead, they fulfill their functions at diverse localities, such as lamella, actomyosin bundles, the Golgi apparatus, focal adhesions, the cell membrane, and within sarcomeres. Sequence comparison of active-site residues and biochemical data available thus far indicate that this myosin class lacks active ATPase-driven motor activity, suggesting that its members function as structural myosins. An emerging body of evidence indicates that this structural capability is essential for the organization, maturation, and regulation of the contractile machinery in both muscle and nonmuscle cells. This is supported by the clear association of myosin-18A (Myo18A) and myosin-18B (Myo18B) dysregulation with diseases such as cancer and various myopathies.
Topics: Actin Cytoskeleton; Actins; Actomyosin; Humans; Muscle Contraction; Myosins
PubMed: 32451870
DOI: 10.1007/978-3-030-38062-5_19 -
Science Translational Medicine Jan 2019The mechanisms by which truncating mutations in (encoding cardiac myosin-binding protein C; cMyBPC) or myosin missense mutations cause hypercontractility and poor...
The mechanisms by which truncating mutations in (encoding cardiac myosin-binding protein C; cMyBPC) or myosin missense mutations cause hypercontractility and poor relaxation in hypertrophic cardiomyopathy (HCM) are incompletely understood. Using genetic and biochemical approaches, we explored how depletion of cMyBPC altered sarcomere function. We demonstrated that stepwise loss of cMyBPC resulted in reciprocal augmentation of myosin contractility. Direct attenuation of myosin function, via a damaging missense variant (F764L) that causes dilated cardiomyopathy (DCM), normalized the increased contractility from cMyBPC depletion. Depletion of cMyBPC also altered dynamic myosin conformations during relaxation, enhancing the myosin state that enables ATP hydrolysis and thin filament interactions while reducing the super relaxed conformation associated with energy conservation. MYK-461, a pharmacologic inhibitor of myosin ATPase, rescued relaxation deficits and restored normal contractility in mouse and human cardiomyocytes with mutations. These data define dosage-dependent effects of cMyBPC on myosin that occur across the cardiac cycle as the pathophysiologic mechanisms by which truncations cause HCM. Therapeutic strategies to attenuate cMyBPC activity may rescue depressed cardiac contractility in patients with DCM, whereas inhibiting myosin by MYK-461 should benefit the substantial proportion of patients with HCM with mutations.
Topics: Adenosine Triphosphate; Animals; Cardiomyopathy, Hypertrophic; Carrier Proteins; Disease Models, Animal; Haploinsufficiency; Humans; Mice; Mutation; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Myosins; Phenotype; ortho-Aminobenzoates
PubMed: 30674652
DOI: 10.1126/scitranslmed.aat1199 -
Advances in Experimental Medicine and... 2020This book, a collection of chapters written by some of the leading researchers in the field of molecular motors, highlights the current understanding of the structure,...
This book, a collection of chapters written by some of the leading researchers in the field of molecular motors, highlights the current understanding of the structure, molecular mechanism, and cellular roles of members of the myosin superfamily. Here, I briefly review the discovery of the first myosin motor, skeletal muscle myosin-II, and preview the contents of subsequent chapters.
Topics: Actins; Muscle, Skeletal; Myosin Type II; Myosins
PubMed: 32451852
DOI: 10.1007/978-3-030-38062-5_1 -
Advances in Experimental Medicine and... 2020The birth of widely available genomic databases at the turn of the millennium led to the identification of many previously unknown myosin genes and identification of... (Review)
Review
The birth of widely available genomic databases at the turn of the millennium led to the identification of many previously unknown myosin genes and identification of novel classes of myosin, including MYO19. Further sequence analysis has revealed the unique evolutionary history of class XIX myosins. MYO19 is found in species ranging from vertebrates to some unicellular organisms, while it has been lost from some lineages containing traditional experimental model organisms. Unique sequences in the motor domain suggest class-specific mechanochemistry that may relate to its cellular function as a mitochondria-associated motor. Work over the past 10 years has demonstrated that MYO19 is an actin-activated ATPase capable of actin-based transport, and investigation of some of the conserved differences within the motor domain indicate their importance in MYO19 motor activity. The cargo-binding MyMOMA tail domain contains two distinct mechanisms of interaction with mitochondrial outer membrane components, and perturbation of MYO19 expression leads to alterations in mitochondrial movement and dynamics that impact cell function. This chapter summarizes the current state of the field and highlights potential new directions of inquiry.
Topics: Actins; Animals; Humans; Mitochondria; Mitochondrial Membranes; Myosins
PubMed: 32451871
DOI: 10.1007/978-3-030-38062-5_20 -
Circulation Mar 2020Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy...
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations.
METHODS
We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias.
RESULTS
Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM.
CONCLUSIONS
Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM.
Topics: Adenosine Triphosphatases; Animals; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Cells, Cultured; Energy Metabolism; Humans; Induced Pluripotent Stem Cells; Mice; Molecular Dynamics Simulation; Muscle Relaxation; Mutation, Missense; Myocardial Contraction; Myocytes, Cardiac; Myosin Heavy Chains; Protein Conformation; Sarcomeres
PubMed: 31983222
DOI: 10.1161/CIRCULATIONAHA.119.042339 -
Advances in Experimental Medicine and... 2020Myosin XVI (Myo16), a vertebrate-specific motor protein, is a recently discovered member of the myosin superfamily. The detailed functionality regarding myosin XVI... (Review)
Review
Myosin XVI (Myo16), a vertebrate-specific motor protein, is a recently discovered member of the myosin superfamily. The detailed functionality regarding myosin XVI requires elucidating or clarification; however, it appears to portray an important role in neural development and in the proper functioning of the nervous system. It is expressed in the largest amount in neural tissues in the late embryonic-early postnatal period, specifically the time in which neuronal cell migration and dendritic elaboration coincide. The impaired expression of myosin XVI has been found lurking in the background of several neuropsychiatric disorders including autism, schizophrenia and/or bipolar disorders.Two principal isoforms of class XVI myosins have been thus far described: Myo16a, the tailless cytoplasmic isoform and Myo16b, the full-length molecule featuring both cytoplasmic and nuclear localization. Both isoforms contain a class-specific N-terminal ankyrin repeat domain that binds to the protein phosphatase catalytic subunit. Myo16b, the predominant isoform, exhibits a diverse function. In the cytoplasm, it participates in the reorganization of the actin cytoskeleton through activation of the PI3K pathway and the WAVE-complex, while in the nucleus it may possess a role in cell cycle regulation. Based on the sequence, myosin XVI may have a compromised ATPase activity, implying a potential stationary role.
Topics: Cell Nucleus; Cytoplasm; Humans; Myosins; Phosphatidylinositol 3-Kinases; Protein Isoforms
PubMed: 32451869
DOI: 10.1007/978-3-030-38062-5_18 -
Experimental Cell Research May 2015Myosin-X (Myo10) is a motor protein best known for its role in filopodia formation. New research implicates Myo10 in a number of disease states including cancer... (Review)
Review
Myosin-X (Myo10) is a motor protein best known for its role in filopodia formation. New research implicates Myo10 in a number of disease states including cancer metastasis and pathogen infection. This review focuses on these developments with emphasis on the emerging roles of Myo10 in formation of cancer cell protrusions and metastasis. A number of aggressive cancers show high levels of Myo10 expression and knockdown of Myo10 has been shown to dramatically limit cancer cell motility in 2D and 3D systems. Myo10 knockdown also limits spread of intracellular pathogens marburgvirus and Shigella flexneri. Consideration is given to how these properties might arise and potential paths of future research.
Topics: Humans; Myosins; Neoplasms
PubMed: 25819274
DOI: 10.1016/j.yexcr.2015.03.014