MYH7 encodes myosin-7, the slow/beta-cardiac myosin heavy chain (beta-MHC, MyHC-slow), a class II sarcomeric myosin and the predominant myosin heavy chain of the human cardiac ventricles and of slow, oxidative type 1 skeletal muscle fibres. Two heavy chains dimerize through a long alpha-helical coiled-coil rod and each binds an essential and a regulatory light chain at the IQ-containing lever arm, forming the hexameric muscle myosin molecule. The N-terminal motor domain is an actin-activated Mg-ATPase: it binds ATP at a P-loop pocket and F-actin through conserved actin-binding loops, and couples ATP hydrolysis to a lever-arm power stroke that slides thin filaments toward the sarcomere centre. The rod, particularly the light meromyosin segment with its 28-residue charge repeats, skip residues and assembly-competent domain, packs into the bipolar thick filaments of the A band. Beta-MHC is a slow, economical motor compared with alpha-MHC (MYH6), and the beta/alpha ratio sets the kinetics and energetic cost of contraction. Its activity is regulated by a folded-back 'interacting-heads motif' in which the two heads lie back on their own S2 tail against the thick-filament backbone; this sequestered state corresponds to a super-relaxed state with very slow ATP turnover, is modulated by myosin-binding protein C and light chain phosphorylation, and is stabilized by the inhibitor mavacamten. Head-domain variants cause hypertrophic cardiomyopathy, frequently by destabilizing the sequestered state, as well as dilated cardiomyopathy and left ventricular non-compaction, whereas variants in the distal rod cause Laing early-onset distal myopathy and myosin storage myopathy by disrupting coiled-coil formation and thick-filament assembly.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000146 microfilament motor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Microfilament motor activity (IBA) is the defining activity of the class II myosin heavy chain clade, which MYH7 sits squarely within. Reason: MYH7 encodes the slow/beta-cardiac class II myosin heavy chain. Its N-terminal motor domain is an actin-activated Mg-ATPase that converts ATP hydrolysis into force and filament sliding; recombinant human beta-cardiac S1 has measurable ATPase, velocity and intrinsic force, and patient beta-myosin moves actin in in vitro motility assays. Microfilament motor activity is the defining core activity. Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction. PMID:23798412 The major change in the R453C human Ξ²-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type PMID:8514894 Mutant beta-myosin, also shown to be present in skeletal muscle by Western blot analysis, translocated actin filaments slower than normal controls in an in vitro motility assay |
| GO:0000146 microfilament motor activity | IDA PMID:15621050 Myocardial contraction is 5-fold more economical in ventricu... | ACCEPT | Summary: Skinned human myocardium: ATP consumption, force and rate of force redevelopment correlate with beta- versus alpha-MHC content, i.e. tissue-level evidence that the beta-MHC motor hydrolyses ATP to generate force. Reason: MYH7 encodes the slow/beta-cardiac class II myosin heavy chain. Its N-terminal motor domain is an actin-activated Mg-ATPase that converts ATP hydrolysis into force and filament sliding; recombinant human beta-cardiac S1 has measurable ATPase, velocity and intrinsic force, and patient beta-myosin moves actin in in vitro motility assays. Microfilament motor activity is the defining core activity. The cited tissue study ties ATP turnover and force kinetics to beta-MHC content; the cached record is abstract-only, so the specific curator inference is deferred to. Supporting Evidence: PMID:15621050 Significant linear correlations were found between MHC isoform composition, ATP consumption and rate of force redevelopment PMID:15621050 In ventricular tissue, the beta-MHC isoform predominates, whereas in atrial tissue a variable mixture of alpha- and beta-MHC is found PMID:23798412 The major change in the R453C human Ξ²-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type |
| GO:0000146 microfilament motor activity | IMP PMID:16088376 Myosin heavy chain composition and the economy of contractio... | ACCEPT | Summary: ATP utilisation and force in human ventricular strips that contain almost exclusively beta-MHC; mutant/composition comparisons support beta-MHC as the force-generating ATPase motor. Reason: MYH7 encodes the slow/beta-cardiac class II myosin heavy chain. Its N-terminal motor domain is an actin-activated Mg-ATPase that converts ATP hydrolysis into force and filament sliding; recombinant human beta-cardiac S1 has measurable ATPase, velocity and intrinsic force, and patient beta-myosin moves actin in in vitro motility assays. Microfilament motor activity is the defining core activity. Abstract-only record; deferring to the curator for the mutant-type (IMP) inference. Supporting Evidence: PMID:16088376 whereas both donor and failing ventricular tissue contained almost exclusively the beta-MHC isoform PMID:16088376 Simultaneous measurements of force and ATP utilisation indicated that economy of contraction is preserved in atrial fibrillation and in end-stage human heart failure PMID:23798412 The major change in the R453C human Ξ²-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type |
| GO:0000146 microfilament motor activity | NAS PMID:3021460 Partial characterization of the human beta-myosin heavy-chai... | ACCEPT | Summary: Early characterization of the human beta-MHC gene and its expression in heart and skeletal muscle; motor activity is asserted by author statement (NAS) from conserved myosin heavy chain function. Reason: MYH7 encodes the slow/beta-cardiac class II myosin heavy chain. Its N-terminal motor domain is an actin-activated Mg-ATPase that converts ATP hydrolysis into force and filament sliding; recombinant human beta-cardiac S1 has measurable ATPase, velocity and intrinsic force, and patient beta-myosin moves actin in in vitro motility assays. Microfilament motor activity is the defining core activity. Supporting Evidence: PMID:3021460 It was demonstrated by the S1 nuclease protection technique that the beta-myosin heavy-chain gene is transcribed in human heart muscle PMID:2249844 The results show that protein subregions responsible for basic functions of myosin heavy chains (nucleotide binding and actin binding) are very similar in homologous and heterologous heavy chains PMID:23798412 The major change in the R453C human Ξ²-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type |
| GO:0001725 stress fiber | IEA GO_REF:0000107 | REMOVE | Summary: Stress fiber, transferred electronically from mouse Myh7 via Ensembl Compara. Reason: Stress fibers are non-muscle actomyosin bundles cross-linked by alpha-actinin and built with non-muscle myosin II (MYH9/MYH10). MYH7 is a sarcomeric myosin whose documented location is the striated-muscle thick filament. A stress-fiber signal for a sarcomeric myosin typically arises from overexpression in non-muscle or immature cultured cells; propagating it electronically to human MYH7 is not supported by any human evidence. Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Note=Thick filaments of the myofibrils. PMID:19336582 Myosin is the molecular motor of muscle and is the major component of the thick filament |
| GO:0002026 regulation of the force of heart contraction | IDA PMID:15621050 Myocardial contraction is 5-fold more economical in ventricu... | MODIFY | Summary: Contractile economy and force kinetics of human myocardium scale with beta-MHC content. Reason: MYH7 is the force-generating motor of ventricular myocardium, so it participates directly in cardiac muscle contraction. 'Regulation of the force of heart contraction' implies a modulatory role (e.g. beta-adrenergic or calcium-handling control); here the data show that the intrinsic properties of the beta-MHC motor set force kinetics and economy, which is execution of contraction, not its regulation. Replace with cardiac muscle contraction. Proposed replacements: cardiac muscle contraction Supporting Evidence: PMID:15621050 Significant linear correlations were found between MHC isoform composition, ATP consumption and rate of force redevelopment PMID:15621050 In ventricular tissue, the beta-MHC isoform predominates, whereas in atrial tissue a variable mixture of alpha- and beta-MHC is found |
| GO:0002027 regulation of heart rate | IDA PMID:15621050 Myocardial contraction is 5-fold more economical in ventricu... | MARK AS OVER ANNOTATED | Summary: Regulation of heart rate, from skinned-tissue measurements of ATP consumption and rate of force redevelopment. Reason: The study measured isometric force and ATP consumption in chemically skinned trabeculae and the rate of force redevelopment (ktr) in single cardiomyocytes. ktr is a cross-bridge cycling rate, not heart rate; heart rate is set by sinoatrial pacemaking and autonomic input, in which a ventricular motor protein plays no part. The annotation appears to map 'rate of force redevelopment' onto heart rate. The cached record is abstract-only, as for the other rows from this paper, so rather than removing a curator's experimental annotation the row is marked over-annotated, matching the treatment of ATP metabolic process from the same paper. Supporting Evidence: PMID:15621050 Isometric force production and ATP consumption were measured in chemically skinned atrial trabeculae and ventricular muscle strips, and rate of force redevelopment was studied using single cardiomyocytes PMID:15621050 Significant linear correlations were found between MHC isoform composition, ATP consumption and rate of force redevelopment |
| GO:0003009 skeletal muscle contraction | IMP PMID:7883988 Abnormal contractile properties of muscle fibers expressing ... | MODIFY | Summary: Single slow-twitch skeletal muscle fibres from HCM patients carrying beta-MHC mutations have altered shortening velocity, force and power. Reason: MYH7 is the motor of type 1 slow skeletal fibres and participates directly in their contraction; the study measured single slow-twitch fibres. Skeletal muscle contraction is correct but the evidence supports the specific child term slow-twitch skeletal muscle fiber contraction. Proposed replacements: slow-twitch skeletal muscle fiber contraction Supporting Evidence: PMID:7883988 As normal and mutant beta-MHCs are expressed in slow-twitch skeletal muscle of HCM patients, we compared the contractile properties of single slow-twitch muscle fibers from patients with three distinct beta-MHC gene mutations and normal controls PMID:7883988 Fibers with the 741Gly-->Arg mutation (near the binding site of essential light chain) demonstrated decreased maximum velocity of shortening (39% of normal) and decreased isometric force generation (42% of normal) PMID:14520662 MYH7 encodes the slow/beta-cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle |
| GO:0003774 cytoskeletal motor activity | IEA GO_REF:0000002 | MODIFY | Summary: Cytoskeletal motor activity from InterPro myosin head domain mapping. Reason: Correct but general: the myosin motor domain moves along actin filaments, so the specific descendant microfilament motor activity (already carried by MYH7 from IBA and experimental rows) is the appropriate term. Proposed replacements: microfilament motor activity Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction. PMID:23798412 The major change in the R453C human Ξ²-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type |
| GO:0005515 protein binding | IPI PMID:17192269 Dissecting the N-terminal myosin binding site of human cardi... | REMOVE | Summary: Interaction of the cardiac MyBP-C C2 domain with the myosin S2 fragment (S2Delta) by NMR/ITC. Reason: Generic protein binding is uninformative. The MyBP-C-S2 interaction is real and is part of how MyBP-C restrains myosin heads, but no informative MF term describes MYH7's side of it (MYH7 is the bound myosin, not a 'myosin binding' protein); removal does not imply that the interaction is false. The regulatory relevance is captured in core_functions and suggested questions. Supporting Evidence: PMID:17192269 Using NMR spectroscopy and isothermal titration calorimetry we demonstrate that cC2 alone binds to a fragment of myosin, S2Delta, with low affinity (kD = 1.1 mM) but exhibits a highly specific binding site PMID:28481356 we show that both S2 and MyBP-C bind to S1 and that phosphorylation of either S1 or MyBP-C weakens these interactions |
| GO:0005515 protein binding | IPI PMID:20847312 Myomasp/LRRC39, a heart- and muscle-specific protein, is a n... | REMOVE | Summary: Yeast two-hybrid and co-IP interaction of the MYH7 C-terminus with the M-band protein myomasp/LRRC39. Reason: Generic protein binding is uninformative; the LRRC39 association places MYH7 rod near the M band but does not identify a specific molecular function of MYH7. Removal does not imply the interaction is false. Supporting Evidence: PMID:20847312 identified the C terminus of myosin heavy chain (MYH)7 as an interaction partner for myomasp |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary yeast two-hybrid interaction with KXD1 (HI-II-14 map). Reason: Generic protein binding from a proteome-scale Y2H screen; KXD1 is a BLOC-1/BORC-related lysosomal positioning factor with no known role in the sarcomere, and the pair has not been studied in muscle. Uninformative for MYH7 function. Supporting Evidence: PMID:25416956 high-quality human binary protein-protein interactions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary yeast two-hybrid interaction with CLVS2 (HuRI map). Reason: Generic protein binding from a proteome-scale Y2H screen; CLVS2 (clavesin 2) is a neuron-specific endosomal protein with no known muscle role. Uninformative for MYH7 function. Supporting Evidence: PMID:32296183 Specifically, yeast two-hybrid (Y2H) represents the only binary PPI assay that can be operated at sufficient throughput to systematically screen the human proteome for binary PPIs. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding from InterPro myosin head mapping (P-loop at residues 178-185). Reason: The myosin motor domain binds MgATP at a conserved P-loop nucleotide-binding pocket (UniProt binding site 178-185), and ATP binding/hydrolysis drives the cross-bridge cycle. Accurate molecular function supporting the core motor activity. Supporting Evidence: PMID:2249844 The results show that protein subregions responsible for basic functions of myosin heavy chains (nucleotide binding and actin binding) are very similar in homologous and heterologous heavy chains PMID:23798412 The major change in the R453C human Ξ²-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: Cytoplasm (IBA, is_active_in) for the class II myosin family. Reason: Correct but very general. MYH7 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band in ventricular cardiomyocytes and type 1 slow skeletal fibres (UniProt: 'Thick filaments of the myofibrils'; rod mutations that impair thick-filament assembly cause myosin storage myopathy). GO:0005863 striated muscle myosin thick filament (part_of sarcomere, is_a myosin filament) is the specific supported location. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN005210253 SUPPORTS TRANSFER Class II myosin ancestral node carrying the general term; MYH7 is correctly inside the clade, so the transfer is valid, but for this sarcomeric isoform a more specific muscle term is supported. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Note=Thick filaments of the myofibrils. PMID:19336582 Myosin is the molecular motor of muscle and is the major component of the thick filament PMID:14520662 Our findings indicate that the mutated residue of slow/beta-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | MODIFY | Summary: Cytoplasm from combined automated methods. Reason: Correct but very general. MYH7 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band in ventricular cardiomyocytes and type 1 slow skeletal fibres (UniProt: 'Thick filaments of the myofibrils'; rod mutations that impair thick-filament assembly cause myosin storage myopathy). GO:0005863 striated muscle myosin thick filament (part_of sarcomere, is_a myosin filament) is the specific supported location. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Note=Thick filaments of the myofibrils. PMID:19336582 Myosin is the molecular motor of muscle and is the major component of the thick filament |
| GO:0005859 muscle myosin complex | TAS PMID:2249844 The complete sequence of the human beta-myosin heavy chain g... | ACCEPT | Summary: Muscle myosin complex, traceable to the complete human beta-MHC gene sequence and comparative analysis. Reason: MYH7 is the heavy chain of the hexameric muscle myosin (two heavy chains, two essential and two regulatory light chains) of ventricular and slow skeletal muscle; muscle myosin complex is the precise complex term. Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). PMID:2249844 The results show that protein subregions responsible for basic functions of myosin heavy chains (nucleotide binding and actin binding) are very similar in homologous and heterologous heavy chains |
| GO:0005859 muscle myosin complex | TAS PMID:3021460 Partial characterization of the human beta-myosin heavy-chai... | ACCEPT | Summary: Muscle myosin complex, traceable to the original characterization of the human beta-MHC gene. Reason: MYH7 is the heavy chain of the hexameric muscle myosin of ventricular and slow skeletal muscle; muscle myosin complex is the precise complex term. Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). PMID:3021460 It was demonstrated by the S1 nuclease protection technique that the beta-myosin heavy-chain gene is transcribed in human heart muscle |
| GO:0006936 muscle contraction | IDA PMID:15621050 Myocardial contraction is 5-fold more economical in ventricu... | MODIFY | Summary: Muscle contraction, from human cardiac tissue mechanics and energetics. Reason: Correct but general. The evidence is from human myocardium, where MYH7 is the predominant ventricular motor, and MYH7 also drives type 1 slow skeletal fibre contraction, so both specific descendants are listed, as for the other muscle contraction row. Proposed replacements: cardiac muscle contraction slow-twitch skeletal muscle fiber contraction Supporting Evidence: PMID:15621050 In ventricular tissue, the beta-MHC isoform predominates, whereas in atrial tissue a variable mixture of alpha- and beta-MHC is found PMID:15621050 Significant linear correlations were found between MHC isoform composition, ATP consumption and rate of force redevelopment |
| GO:0006936 muscle contraction | TAS PMID:15856146 Prevalence of cardiac beta-myosin heavy chain gene mutations... | MODIFY | Summary: Muscle contraction, traceable to an MYH7 mutation-screening study in HCM. Reason: Correct but general. MYH7 directly drives contraction of both ventricular myocardium and type 1 slow skeletal fibres, so both specific descendants are listed. Proposed replacements: cardiac muscle contraction slow-twitch skeletal muscle fiber contraction Supporting Evidence: PMID:15856146 Mutations in the cardiac beta-myosin heavy chain gene (MYH7) are responsible for the disease in about 30% of cases where mutations were identified PMID:14520662 MYH7 encodes the slow/beta-cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle PMID:14520662 It is also the major MyHC isoform of cardiac ventricles |
| GO:0006941 striated muscle contraction | IDA PMID:15621050 Myocardial contraction is 5-fold more economical in ventricu... | MODIFY | Summary: Striated muscle contraction, from human cardiac tissue mechanics. Reason: Correct but general for evidence obtained in human myocardium; replace with cardiac muscle contraction. Proposed replacements: cardiac muscle contraction Supporting Evidence: PMID:15621050 In ventricular tissue, the beta-MHC isoform predominates, whereas in atrial tissue a variable mixture of alpha- and beta-MHC is found PMID:15621050 Significant linear correlations were found between MHC isoform composition, ATP consumption and rate of force redevelopment |
| GO:0007512 adult heart development | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Adult heart development (IBA) propagated across the sarcomeric myosin clade. Reason: MYH7 is a contractile motor and structural thick-filament protein. Hypertrophy, dilatation and non-compaction in MYH7 variant carriers show that normal myosin function is necessary for normal adult myocardial structure, but the myosin does not carry out developmental steps; these are secondary remodeling responses to altered contractility. Necessity evidence of this kind does not establish participation in heart development. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002897290 SUPPORTS SOURCE BUT NOT TARGET Sarcomeric myosin node that also carries muscle filament sliding and cardiac muscle contraction; MYH7 is inside the clade, but the developmental term rests on contractile-dysfunction phenotypes (necessity) rather than on the myosin performing developmental work. Supporting Evidence: PMID:7883988 These functional alterations likely constitute the primary stimulus for the cardiac hypertrophy that is characteristic of this disease PMID:15856146 Mutations in the cardiac beta-myosin heavy chain gene (MYH7) are responsible for the disease in about 30% of cases where mutations were identified |
| GO:0007512 adult heart development | IMP PMID:15856146 Prevalence of cardiac beta-myosin heavy chain gene mutations... | MARK AS OVER ANNOTATED | Summary: Adult heart development, from a clinical MYH7 mutation-prevalence study in hypertrophic cardiomyopathy. Reason: The study is a genetic screen of HCM patients; it shows MYH7 mutations cause left ventricular hypertrophy, a disease phenotype that arises as a remodeling response to abnormal myosin function. Converting this phenotype into a developmental process term over-annotates a contractile motor. Supporting Evidence: PMID:15856146 Mutations in the cardiac beta-myosin heavy chain gene (MYH7) are responsible for the disease in about 30% of cases where mutations were identified PMID:7883988 These functional alterations likely constitute the primary stimulus for the cardiac hypertrophy that is characteristic of this disease |
| GO:0014728 regulation of the force of skeletal muscle contraction | IMP PMID:7883988 Abnormal contractile properties of muscle fibers expressing ... | MODIFY | Summary: Force and velocity of slow-twitch skeletal fibres carrying beta-MHC mutations. Reason: The beta-MHC motor generates the force of slow fibres rather than regulating it from outside the contractile machinery; the mutant-fibre data show altered execution of contraction. Replace with slow-twitch skeletal muscle fiber contraction. Proposed replacements: slow-twitch skeletal muscle fiber contraction Supporting Evidence: PMID:7883988 As normal and mutant beta-MHCs are expressed in slow-twitch skeletal muscle of HCM patients, we compared the contractile properties of single slow-twitch muscle fibers from patients with three distinct beta-MHC gene mutations and normal controls PMID:7883988 Fibers with the 741Gly-->Arg mutation (near the binding site of essential light chain) demonstrated decreased maximum velocity of shortening (39% of normal) and decreased isometric force generation (42% of normal) |
| GO:0016459 myosin complex | IEA GO_REF:0000120 | MODIFY | Summary: Myosin complex from automated methods (InterPro/ortholog). Reason: Correct but general; MYH7 is the heavy chain of the hexameric muscle myosin, so the descendant muscle myosin complex (already carried from TAS rows) is the specific term. Proposed replacements: muscle myosin complex Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). |
| GO:0016459 myosin complex | TAS PMID:12933792 Single-stranded DNA-binding proteins PURalpha and PURbeta bi... | MODIFY | Summary: Myosin complex, traceable to a paper on transcriptional/translational control of the paralog alpha-MHC (MYH6) by PUR proteins. Reason: The cited abstract concerns alpha-MHC regulation and describes MHC as a principal thick-filament molecule, which is equally true of beta-MHC; the statement is correct for MYH7 but general. Replace with muscle myosin complex, the precise complex term. Proposed replacements: muscle myosin complex Supporting Evidence: PMID:12933792 The alpha-myosin heavy chain is a principal molecule of the thick filament of the sarcomere, expressed primarily in cardiac myocytes file:human/MYH7/MYH7-uniprot.txt Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). |
| GO:0016460 myosin II complex | IBA GO_REF:0000033 | MODIFY | Summary: Myosin II complex (IBA) for the class II myosin clade. Reason: Correct (MYH7 is a class II myosin heavy chain) but the muscle-specific child term muscle myosin complex, already carried from TAS rows, is supported for this sarcomeric isoform. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN005210253 SUPPORTS TRANSFER Class II myosin ancestral node carrying the general term; MYH7 is correctly inside the clade, so the transfer is valid, but for this sarcomeric isoform a more specific muscle term is supported. Proposed replacements: muscle myosin complex Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). PMID:19336582 Myosin is the molecular motor of muscle and is the major component of the thick filament |
| GO:0016460 myosin II complex | IEA GO_REF:0000117 | MODIFY | Summary: Myosin II complex from ARBA. Reason: Correct but general; replace with muscle myosin complex. Proposed replacements: muscle myosin complex Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). |
| GO:0030016 myofibril | IEA GO_REF:0000120 | MODIFY | Summary: Myofibril, from automated methods. Reason: Correct but general. MYH7 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band in ventricular cardiomyocytes and type 1 slow skeletal fibres (UniProt: 'Thick filaments of the myofibrils'; rod mutations that impair thick-filament assembly cause myosin storage myopathy). GO:0005863 striated muscle myosin thick filament (part_of sarcomere, is_a myosin filament) is the specific supported location. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Note=Thick filaments of the myofibrils. PMID:19336582 Myosin is the molecular motor of muscle and is the major component of the thick filament |
| GO:0030016 myofibril | ISS GO_REF:0000024 | MODIFY | Summary: Myofibril by sequence similarity to rat Myh7. Reason: Correct but general. MYH7 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band in ventricular cardiomyocytes and type 1 slow skeletal fibres (UniProt: 'Thick filaments of the myofibrils'; rod mutations that impair thick-filament assembly cause myosin storage myopathy). GO:0005863 striated muscle myosin thick filament (part_of sarcomere, is_a myosin filament) is the specific supported location. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Note=Thick filaments of the myofibrils. file:human/MYH7/MYH7-uniprot.txt Forms regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle. |
| GO:0030017 sarcomere | IEA GO_REF:0000044 | MODIFY | Summary: Sarcomere from UniProt subcellular-location mapping. Reason: Correct but general. MYH7 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band in ventricular cardiomyocytes and type 1 slow skeletal fibres (UniProt: 'Thick filaments of the myofibrils'; rod mutations that impair thick-filament assembly cause myosin storage myopathy). GO:0005863 striated muscle myosin thick filament (part_of sarcomere, is_a myosin filament) is the specific supported location. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Note=Thick filaments of the myofibrils. file:human/MYH7/MYH7-uniprot.txt Forms regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle. |
| GO:0030017 sarcomere | ISS GO_REF:0000024 | MODIFY | Summary: Sarcomere by sequence similarity to rat Myh7. Reason: Correct but general. MYH7 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band in ventricular cardiomyocytes and type 1 slow skeletal fibres (UniProt: 'Thick filaments of the myofibrils'; rod mutations that impair thick-filament assembly cause myosin storage myopathy). GO:0005863 striated muscle myosin thick filament (part_of sarcomere, is_a myosin filament) is the specific supported location. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Note=Thick filaments of the myofibrils. file:human/MYH7/MYH7-uniprot.txt Forms regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle. |
| GO:0030017 sarcomere | TAS PMID:16754800 Single-gene mutations and increased left ventricular wall th... | MODIFY | Summary: Sarcomere, traceable to a community study of sarcomere protein gene mutations and LV wall thickness. Reason: Correct but general; the paper treats MYH7 as a sarcomere protein gene. MYH7 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band in ventricular cardiomyocytes and type 1 slow skeletal fibres (UniProt: 'Thick filaments of the myofibrils'; rod mutations that impair thick-filament assembly cause myosin storage myopathy). GO:0005863 striated muscle myosin thick filament (part_of sarcomere, is_a myosin filament) is the specific supported location. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: PMID:16754800 7 mutations in 5 sarcomere protein genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL3) file:human/MYH7/MYH7-uniprot.txt Note=Thick filaments of the myofibrils. PMID:19336582 Myosin is the molecular motor of muscle and is the major component of the thick filament |
| GO:0030018 Z disc | IEA GO_REF:0000107 | REMOVE | Summary: Z disc, transferred electronically from mouse Myh7 via Ensembl Compara. Reason: Myosin thick filaments occupy the A band and are cross-linked at the M band; the Z disc anchors the barbed ends of actin thin filaments and is not a site of the myosin heavy chain. No human evidence places MYH7 at the Z disc, and the projection is inconsistent with sarcomere architecture. Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Note=Thick filaments of the myofibrils. PMID:19336582 Myosin is the molecular motor of muscle and is the major component of the thick filament |
| GO:0030049 muscle filament sliding | IBA GO_REF:0000033 | ACCEPT | Summary: Muscle filament sliding (IBA) for the sarcomeric myosin II clade. Reason: The beta-myosin heads cyclically bind actin thin filaments and pull them past the thick filament; filament sliding is the process MYH7 executes directly in heart and slow muscle. Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Forms regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle. PMID:8514894 Mutant beta-myosin, also shown to be present in skeletal muscle by Western blot analysis, translocated actin filaments slower than normal controls in an in vitro motility assay PMID:7883988 Fibers with the 741Gly-->Arg mutation (near the binding site of essential light chain) demonstrated decreased maximum velocity of shortening (39% of normal) and decreased isometric force generation (42% of normal) |
| GO:0030049 muscle filament sliding | IMP PMID:16088376 Myosin heavy chain composition and the economy of contractio... | ACCEPT | Summary: Force and ATP utilisation of human myocardium dominated by beta-MHC. Reason: MYH7 drives filament sliding in ventricular myocardium. Abstract-only record; deferring to the curator's IMP inference. Supporting Evidence: PMID:16088376 whereas both donor and failing ventricular tissue contained almost exclusively the beta-MHC isoform PMID:16088376 Simultaneous measurements of force and ATP utilisation indicated that economy of contraction is preserved in atrial fibrillation and in end-stage human heart failure file:human/MYH7/MYH7-uniprot.txt Forms regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle. |
| GO:0030049 muscle filament sliding | IMP PMID:8514894 Skeletal muscle expression and abnormal function of beta-myo... | ACCEPT | Summary: Mutant beta-myosin purified from patient skeletal muscle translocates actin filaments more slowly in in vitro motility assays. Reason: Direct evidence that the MYH7 motor drives actin filament sliding and that a missense mutation impairs it. Supporting Evidence: PMID:8514894 Mutant beta-myosin, also shown to be present in skeletal muscle by Western blot analysis, translocated actin filaments slower than normal controls in an in vitro motility assay PMID:8514894 single amino acid changes in beta-myosin result in abnormal actomyosin interactions |
| GO:0031449 regulation of slow-twitch skeletal muscle fiber contraction | IMP PMID:7883988 Abnormal contractile properties of muscle fibers expressing ... | MODIFY | Summary: Contractile properties of single slow-twitch fibres carrying beta-MHC mutations. Reason: MYH7 is the motor of the slow-twitch fibre and executes its contraction; it is not a regulator acting on that contraction. Replace with slow-twitch skeletal muscle fiber contraction. Proposed replacements: slow-twitch skeletal muscle fiber contraction Supporting Evidence: PMID:7883988 As normal and mutant beta-MHCs are expressed in slow-twitch skeletal muscle of HCM patients, we compared the contractile properties of single slow-twitch muscle fibers from patients with three distinct beta-MHC gene mutations and normal controls PMID:7883988 Fibers with the 741Gly-->Arg mutation (near the binding site of essential light chain) demonstrated decreased maximum velocity of shortening (39% of normal) and decreased isometric force generation (42% of normal) |
| GO:0032982 myosin filament | IBA GO_REF:0000033 | MODIFY | Summary: Myosin filament (IBA, is_active_in) for the class II myosin clade. Reason: Correct but general for a sarcomeric myosin. MYH7 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band in ventricular cardiomyocytes and type 1 slow skeletal fibres (UniProt: 'Thick filaments of the myofibrils'; rod mutations that impair thick-filament assembly cause myosin storage myopathy). GO:0005863 striated muscle myosin thick filament (part_of sarcomere, is_a myosin filament) is the specific supported location. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN005210253 SUPPORTS TRANSFER Class II myosin ancestral node carrying the general term; MYH7 is correctly inside the clade, so the transfer is valid, but for this sarcomeric isoform a more specific muscle term is supported. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: PMID:19336582 Although the head region is responsible for myosin's ATPase and actin binding properties, the rod region functions to incorporate myosin into bipolar thick filaments through charge based interactions between adjacent rods PMID:14520662 Our findings indicate that the mutated residue of slow/beta-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle |
| GO:0032982 myosin filament | IDA PMID:19336582 Mutations in the beta-myosin rod cause myosin storage myopat... | MODIFY | Summary: Recombinant MYH7 light meromyosin self-assembles into ordered paracrystals whose 14 nm periodicity matches the axial spacing of beta-MyHC in native bipolar thick filaments; myosin storage myopathy mutations alter assembly. Reason: The direct data show that the MYH7 rod assembles into myosin filaments, and the paper relates this to native bipolar thick filaments of muscle. MYH7 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band in ventricular cardiomyocytes and type 1 slow skeletal fibres (UniProt: 'Thick filaments of the myofibrils'; rod mutations that impair thick-filament assembly cause myosin storage myopathy). GO:0005863 striated muscle myosin thick filament (part_of sarcomere, is_a myosin filament) is the specific supported location. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: PMID:19336582 corresponds well to the 14.3 nm axial spacing of full-length Ξ²-MyHC found in bipolar thick filaments PMID:19336582 Although the head region is responsible for myosin's ATPase and actin binding properties, the rod region functions to incorporate myosin into bipolar thick filaments through charge based interactions between adjacent rods PMID:19336582 Myosin is the molecular motor of muscle and is the major component of the thick filament |
| GO:0046034 ATP metabolic process | IDA PMID:15621050 Myocardial contraction is 5-fold more economical in ventricu... | MARK AS OVER ANNOTATED | Summary: ATP metabolic process, from measurements of ATP consumption by skinned human myocardium. Reason: The ATP consumption measured is myosin's ATP hydrolysis during force generation, which is captured by the molecular function microfilament motor activity. Myosin is not part of an ATP metabolic pathway in the GO sense (synthesis, salvage or catabolism for metabolic purposes); annotating every ATPase to ATP metabolic process over-annotates. Supporting Evidence: PMID:15621050 Significant linear correlations were found between MHC isoform composition, ATP consumption and rate of force redevelopment PMID:15621050 Isometric force production and ATP consumption were measured in chemically skinned atrial trabeculae and ventricular muscle strips, and rate of force redevelopment was studied using single cardiomyocytes |
| GO:0051015 actin filament binding | IBA GO_REF:0000033 | ACCEPT | Summary: Actin filament binding (IBA) for the myosin II clade. Reason: The motor domain binds F-actin via conserved actin-binding loops (UniProt regions 655-677 and 757-771); strong actin binding is a step of every cross-bridge cycle. Supporting Evidence: PMID:19336582 Although the head region is responsible for myosin's ATPase and actin binding properties, the rod region functions to incorporate myosin into bipolar thick filaments through charge based interactions between adjacent rods PMID:2249844 The results show that protein subregions responsible for basic functions of myosin heavy chains (nucleotide binding and actin binding) are very similar in homologous and heterologous heavy chains PMID:31213605 lead to a significant increase in the number of heads functionally accessible for interaction with actin |
| GO:0051015 actin filament binding | IEA GO_REF:0000002 | ACCEPT | Summary: Actin filament binding from InterPro. Reason: Accurate: the myosin head binds actin filaments as part of the motor cycle. Supporting Evidence: PMID:19336582 Although the head region is responsible for myosin's ATPase and actin binding properties, the rod region functions to incorporate myosin into bipolar thick filaments through charge based interactions between adjacent rods PMID:2249844 The results show that protein subregions responsible for basic functions of myosin heavy chains (nucleotide binding and actin binding) are very similar in homologous and heterologous heavy chains |
| GO:0055010 ventricular cardiac muscle tissue morphogenesis | IMP PMID:15856146 Prevalence of cardiac beta-myosin heavy chain gene mutations... | MARK AS OVER ANNOTATED | Summary: Ventricular cardiac muscle tissue morphogenesis, from an HCM mutation-prevalence study. Reason: The paper reports MYH7 mutations in patients with left ventricular hypertrophy. Hypertrophic remodeling in adults is a pathological response to abnormal contractility, not morphogenesis, and MYH7 performs no morphogenetic step. Ventricular non-compaction in some MYH7 carriers likewise indicates necessity of normal myosin function, not participation in tissue morphogenesis. Supporting Evidence: PMID:15856146 Mutations in the cardiac beta-myosin heavy chain gene (MYH7) are responsible for the disease in about 30% of cases where mutations were identified PMID:18506004 MYH7 mutations segregated with the disease in 4 autosomal dominant LVNC kindreds |
| GO:0055010 ventricular cardiac muscle tissue morphogenesis | IMP PMID:16754800 Single-gene mutations and increased left ventricular wall th... | MARK AS OVER ANNOTATED | Summary: Ventricular cardiac muscle tissue morphogenesis, from a community study linking sarcomere gene mutations to increased LV wall thickness. Reason: Increased LV wall thickness in adult mutation carriers is a disease phenotype (hypertrophic remodeling), not ventricular tissue morphogenesis; MYH7 contributes contractile force, not morphogenetic activity. Supporting Evidence: PMID:16754800 7 mutations in 5 sarcomere protein genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL3) PMID:15856146 Mutations in the cardiac beta-myosin heavy chain gene (MYH7) are responsible for the disease in about 30% of cases where mutations were identified |
| GO:0060048 cardiac muscle contraction | IBA GO_REF:0000033 | ACCEPT | Summary: Cardiac muscle contraction (IBA) for the sarcomeric myosin clade. Reason: MYH7 is the predominant myosin heavy chain of human ventricles and directly generates the force of ventricular contraction. Supporting Evidence: PMID:14520662 It is also the major MyHC isoform of cardiac ventricles PMID:15621050 In ventricular tissue, the beta-MHC isoform predominates, whereas in atrial tissue a variable mixture of alpha- and beta-MHC is found PMID:23798412 The major change in the R453C human Ξ²-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type |
| GO:0060048 cardiac muscle contraction | IMP PMID:7883988 Abnormal contractile properties of muscle fibers expressing ... | ACCEPT | Summary: beta-MHC mutations alter the contractile properties of slow-twitch fibres from HCM patients, used as a surrogate for the cardiac motor. Reason: Although the measurements were made on slow skeletal fibres expressing the same beta-MHC, the authors relate the altered contractility directly to the cardiac disease; together with direct data on human beta-cardiac S1 and ventricular tissue, MYH7 is a core participant in cardiac muscle contraction. Supporting Evidence: PMID:7883988 As normal and mutant beta-MHCs are expressed in slow-twitch skeletal muscle of HCM patients, we compared the contractile properties of single slow-twitch muscle fibers from patients with three distinct beta-MHC gene mutations and normal controls PMID:7883988 These functional alterations likely constitute the primary stimulus for the cardiac hypertrophy that is characteristic of this disease PMID:23798412 The major change in the R453C human Ξ²-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type |
| GO:0099512 supramolecular fiber | IEA GO_REF:0000117 | MODIFY | Summary: Supramolecular fiber from ARBA. Reason: Correct but very general. MYH7 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band in ventricular cardiomyocytes and type 1 slow skeletal fibres (UniProt: 'Thick filaments of the myofibrils'; rod mutations that impair thick-filament assembly cause myosin storage myopathy). GO:0005863 striated muscle myosin thick filament (part_of sarcomere, is_a myosin filament) is the specific supported location. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: file:human/MYH7/MYH7-uniprot.txt Note=Thick filaments of the myofibrils. PMID:19336582 Myosin is the molecular motor of muscle and is the major component of the thick filament |
| GO:0008307 structural constituent of muscle | IDA PMID:19336582 Mutations in the beta-myosin rod cause myosin storage myopat... | NEW | Summary: The MYH7 rod (light meromyosin) is the building block of the striated-muscle thick filament backbone; rod variants that impair coiled-coil formation or filament assembly cause myosin storage myopathy and Laing distal myopathy. Reason: Besides its motor activity, MYH7 is the principal structural component of the thick filaments of ventricular and slow skeletal muscle: its rod self-assembles into bipolar filaments through charged 28-residue repeats, skip residues and the assembly-competent domain. Comparator check (QuickGO): other muscle myosin heavy chains already carry GO:0008307, namely human MYH8 (NAS, PMID:2715179), human MYH11 (IMP, PMID:16444274), C. elegans unc-54 (IDA, PMID:3320053) and Drosophila Mhc (IMP, PMID:8995523), so this is an established convention that MYH7 lacks rather than a novel use of the term. Supporting Evidence: PMID:19336582 Although the head region is responsible for myosin's ATPase and actin binding properties, the rod region functions to incorporate myosin into bipolar thick filaments through charge based interactions between adjacent rods PMID:14520662 Our findings indicate that the mutated residue of slow/beta-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle PMID:26150528 The rod of sarcomeric myosins directs thick filament assembly and is characterized by the insertion of four skip residues that introduce discontinuities in the coiled-coil heptad repeats file:human/MYH7/MYH7-uniprot.txt Forms regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle. |
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Download this section (compressed HTML)Q: GO has no term for the regulated sequestration of myosin heads in the interacting-heads motif / super-relaxed state, a property of the MYH7 motor itself (stabilized by intramolecular head-head and head-S2 interfaces, released by HCM mutations and phosphorylation, and pharmacologically targeted by mavacamten). Should a molecular function or process term be created so that this regulated state can be annotated to cardiac and other class II myosins?
Suggested experts: GO editors, cardiac myosin biophysicists
Q: How is the balance between the super-relaxed (IHM) and disordered-relaxed states of beta-cardiac myosin controlled in vivo, and how much of it is set by MYH7 itself versus MyBP-C, titin and regulatory light chain phosphorylation?
Suggested experts: muscle physiologists, structural biologists of the thick filament
Q: Why do distal-rod MYH7 variants produce skeletal myopathies (Laing distal myopathy, myosin storage myopathy) usually without cardiomyopathy, despite the same protein being abundant in ventricular thick filaments?
Suggested experts: neuromuscular geneticists, myosin rod assembly specialists
Q: Should myosin heavy chains themselves carry striated muscle myosin thick filament assembly (GO:0071688)? Their rods self-assemble into the filament, but current annotations of this term go to assembly factors (UNC-45, UNC-89, MyBP-C) rather than to the myosins.
Suggested experts: GO editors, GOA curators
Experiment: Quantify the fraction of beta-cardiac myosin heads in the super-relaxed state (mant-ATP single turnover) and in the ordered off state (X-ray diffraction) in human iPSC-cardiomyocytes or engineered heart tissue carrying HCM, DCM and LVNC head-domain variants, with and without mavacamten.
Hypothesis: HCM variants reduce, and DCM variants increase or leave unchanged, the sequestered head fraction.
Type: biochemical and structural assays in isogenic human cardiomyocyte models
Experiment: Express full-length MYH7 carrying Laing distal myopathy and myosin storage myopathy rod variants in cardiomyocytes and slow skeletal myotubes and compare thick-filament incorporation, turnover and aggregation by live imaging and proteomics.
Hypothesis: Rod variants impair thick-filament incorporation or degradation in a cell-type-dependent manner that explains skeletal-predominant disease.
Type: cell-based assembly and turnover assays
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