MYH2 encodes myosin-2, the fast type IIa skeletal muscle myosin heavy chain (MyHC-IIa, MyHC-2a), a class II sarcomeric myosin and the major myosin heavy chain of fast, oxidative type 2A fibres of adult human skeletal muscle. It is not a cardiac isoform. 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. Recombinant human MyHC-IIa has actin-activated ATPase and actin motility rates slower than the IId (IIx) and IIb isoforms, matching the intermediate shortening velocity of type 2A fibres, which contract faster than slow type 1 fibres and more slowly than type 2X fibres. The rod, particularly the light meromyosin segment with its 28-residue charge repeats, packs into the bipolar thick filaments of the A band, on which the heads can fold back into a sequestered, energy-sparing super-relaxed state. Dominant variants in the motor domain (notably E706K in the SH1 helix) and in the rod, and recessive missense or truncating variants that abolish MyHC-IIa expression, cause MYH2-related congenital myopathy with external ophthalmoplegia; light meromyosin variants disrupt coiled-coil and filament packing and reduce the super-relaxed state in patient fibres.
| 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 MYH2 sits squarely within. Reason: MYH2 encodes the fast type IIa 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 MyHC-IIa expressed in muscle cells has measurable actin-activated ATPase activity and moves actin filaments in motility assays, and patient fibres carrying the motor-domain variant E706K show severely impaired IIa motor function. Microfilament motor activity is the defining core activity. Supporting Evidence: file:human/MYH2/MYH2-uniprot.txt Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction. PMID:20080549 In this study we describe a mammalian muscle cell expression system and the functional analysis of all six recombinant human type II skeletal muscle myosin isoforms. PMID:20080549 MyHC-IIb displays the highest maximal actin-activated ATPase rate, and the rates for the adult-fast isoforms follow the order from fastest to slowest: MyHC-IIb > MyHC-IId > MyHC-IIa PMID:17005402 A dramatic impairment in the function of the IIa MyHC isoform was observed at the motor protein level. |
| GO:0000146 microfilament motor activity | TAS PMID:10388558 Comparative sequence analysis of the complete human sarcomer... | ACCEPT | Summary: Microfilament motor activity, traceable to the comparative sequence analysis of the complete human sarcomeric myosin heavy chain family, which first reported the full MyHC-IIa coding sequence. Reason: The cited paper frames the sarcomeric MyHCs, including MyHC-IIa, as the motor proteins that drive skeletal muscle contraction; direct biochemistry on recombinant human MyHC-IIa confirms actin-activated ATPase and motility. Microfilament motor activity is the core activity. Supporting Evidence: PMID:10388558 The conventional myosin motor proteins that drive mammalian skeletal and cardiac muscle contraction include eight sarcomeric myosin heavy chain (MyHC) isoforms. PMID:10388558 we present new full-length coding sequences corresponding to four additional human genes: MyHC-IIb, MyHC-extraocular, MyHC-IIa and MyHC-IIx/d PMID:20080549 Our data also show that ATPase activity and motility are generally correlated for human skeletal muscle myosins. |
| GO:0003008 system process | IEA GO_REF:0000117 | MODIFY | Summary: System process, from an ARBA machine-learning rule. Reason: Correct but extremely general: the system process MYH2 executes is skeletal muscle contraction, specifically the contraction of fast type 2A fibres in which MyHC-IIa is the major myosin. Replace with fast-twitch skeletal muscle fiber contraction (GO:0031443), the specific descendant also proposed for the muscle contraction rows of this review. Proposed replacements: fast-twitch skeletal muscle fiber contraction Supporting Evidence: PMID:22918376 MyHC IIa (MYH2) is expressed in fast, type 2A muscle fibers PMID:37788100 Myosin heavy chains encoded by MYH7 and MYH2 are abundant in human skeletal muscle and important for muscle contraction. |
| 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 MYH2 from IBA and TAS rows) is the appropriate term. Proposed replacements: microfilament motor activity Supporting Evidence: file:human/MYH2/MYH2-uniprot.txt Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction. PMID:20080549 Our data also show that ATPase activity and motility are generally correlated for human skeletal muscle myosins. |
| GO:0005515 protein binding | IPI PMID:17823310 HGAL, a lymphoma prognostic biomarker, interacts with the cy... | REMOVE | Summary: Interaction of the germinal-centre B-cell adaptor HGAL (GCSAM) with myosin II in lymphoma cells. Reason: Generic protein binding is uninformative. The study describes HGAL as an adaptor that binds actin and myosin II in B-cell lymphoma lines; the informative molecular function belongs to HGAL, not to the myosin, and the myosin II of lymphocytes is expected to be non-muscle myosin II rather than the fast skeletal MyHC-IIa. Removal does not imply that the reported interaction is false. Supporting Evidence: PMID:17823310 We showed that HGAL functions as an adaptor binding actin and myosin II proteins, and demonstrated that its N-terminal portion is sufficient for these interactions. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding from InterPro myosin head mapping (P-loop at residues 179-186). Reason: The myosin motor domain binds MgATP at a conserved P-loop nucleotide-binding pocket (UniProt binding site 179-186), and ATP binding and hydrolysis drive the cross-bridge cycle; recombinant MyHC-IIa is an active ATPase. Accurate molecular function supporting the core motor activity. Supporting Evidence: PMID:20080549 MyHC-IIb displays the highest maximal actin-activated ATPase rate, and the rates for the adult-fast isoforms follow the order from fastest to slowest: MyHC-IIb > MyHC-IId > MyHC-IIa PMID:23908353 Here we study purified recombinant human myosin motor domains expressed in mouse C2C12 muscle cells. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: Cytoplasm (IBA, is_active_in) for the myosin family. Reason: Correct but very general. MYH2 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band of fast type 2A skeletal fibres (UniProt: 'Thick filaments of the myofibrils'; MYH2 light meromyosin variants disrupt coiled-coil structure and filament packing). GO:0005863 striated muscle myosin thick filament (part_of sarcomere, is_a myosin filament) is the specific supported location, as chosen for the paralog MYH7. 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; MYH2 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/MYH2/MYH2-uniprot.txt Note=Thick filaments of the myofibrils. PMID:22918376 The myosin heavy chain (MyHC) is the molecular motor of muscle and forms the backbone of the sarcomere thick filaments. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2029476 | REMOVE | Summary: Cytosol, from the Reactome pathway 'Role of myosins in phagosome formation'. Reason: The Reactome event describes non-muscle myosin II acting at the forming phagocytic cup of FCGR-engaged phagocytes; MYH2 is included only as a member of the generic myosin II heavy-chain set. MyHC-IIa is a fast skeletal muscle isoform that is not expressed in phagocytes, and its documented location is the thick filament of the myofibril rather than the soluble cytosol. The location is an artefact of placing every class II heavy chain into a non-muscle reaction and is not supported for MYH2. Supporting Evidence: Reactome:R-HSA-2029476 Nonmuscle myosin II, is a motor protein known to generate intracellular contractile forces and tension by associating with F-actin. PMID:22918376 MyHC IIa (MYH2) is expressed in fast, type 2A muscle fibers file:human/MYH2/MYH2-uniprot.txt Note=Thick filaments of the myofibrils. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9666458 | REMOVE | Summary: Cytosol, from a Reactome reaction in which FCGR3A translocates to the Leishmania parasitophorous vacuole during macrophage phagocytosis. Reason: This reaction belongs to the macrophage response to Leishmania, which uses non-muscle myosin II at the phagocytic cup; MYH2 enters it only as a member of the generic myosin II heavy-chain set. MyHC-IIa is restricted to fast skeletal muscle fibres and resides in thick filaments, so a cytosolic location in phagocytes is not supported. Supporting Evidence: Reactome:R-HSA-2029476 Nonmuscle myosin II, is a motor protein known to generate intracellular contractile forces and tension by associating with F-actin. PMID:22918376 MyHC IIa (MYH2) is expressed in fast, type 2A muscle fibers |
| GO:0005859 muscle myosin complex | NAS PMID:3904738 The myosin alkali light chain proteins and their genes. | ACCEPT | Summary: Muscle myosin complex, by author statement in a 1985 review of myosin alkali light chains and their genes. Reason: MYH2 is the heavy chain of the hexameric muscle myosin (two heavy chains, two essential and two regulatory light chains) of fast type 2A fibres; muscle myosin complex is the precise complex term, and the light-chain review describes the subunits of that hexamer. The cached record has no abstract, so the specific statement used by the curator could not be read; the assertion is consistent with established muscle myosin structure. Supporting Evidence: file:human/MYH2/MYH2-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:0005859 muscle myosin complex | TAS PMID:10388558 Comparative sequence analysis of the complete human sarcomer... | ACCEPT | Summary: Muscle myosin complex, traceable to the complete sequence analysis of the human sarcomeric myosin heavy chain family. Reason: MYH2 is the heavy chain of the hexameric muscle myosin of fast type 2A fibres; muscle myosin complex is the precise complex term. Supporting Evidence: file:human/MYH2/MYH2-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:10388558 The conventional myosin motor proteins that drive mammalian skeletal and cardiac muscle contraction include eight sarcomeric myosin heavy chain (MyHC) isoforms. |
| GO:0005911 cell-cell junction | IMP PMID:25753039 ZO-1 controls endothelial adherens junctions, cell-cell tens... | REMOVE | Summary: Cell-cell junction, from a study of ZO-1 depletion in primary human dermal microvascular endothelial cells, where junctional 'myosin IIA' redistributed to stress fibres. Reason: The cached full text shows that the protein studied is the junctional actomyosin of endothelial cells (HDMEC), detected with an anti-myosin IIA antibody. In that context 'myosin IIA' is non-muscle myosin IIA, the product of MYH9, not the fast skeletal muscle myosin heavy chain IIa encoded by MYH2: the names collide, but the proteins are different genes, and MyHC-IIa is restricted to fast type 2A skeletal fibres. Consistent with a name-based mis-mapping, this reference appears on the MYH2 GOA file but not on MYH9's. The annotation should be transferred to MYH9 (non-muscle myosin IIA), not kept on MYH2. Supporting Evidence: PMID:25753039 Here, we asked whether ZO-1 is important for endothelial integrity and function in primary human dermal microvascular EC (HDMEC) and whether it regulates angiogenic properties of EC PMID:25753039 In control HDMEC, Ξ²-actin and myosin IIA formed a junctional belt that was positive for double phosphorylated myosin light chain 2 (MLC2), which indicates that myosin was active PMID:22918376 The non-muscle conventional class II MyHC genes MYH9 and MYH10 encode the non-muscle myosins IIA (MYHIIA) and IIB (MYHIIB), whereas MYH11 encodes smooth muscle MyHC. PMID:22918376 MyHC IIa (MYH2) is expressed in fast, type 2A muscle fibers |
| GO:0006936 muscle contraction | IBA GO_REF:0000033 | MODIFY | Summary: Muscle contraction (IBA) for the skeletal sarcomeric myosin clade. Reason: Correct but general. MYH2 is the motor of fast type 2A skeletal fibres and directly drives their contraction; the specific supported descendant is fast-twitch skeletal muscle fiber contraction, matching the choice of slow-twitch skeletal muscle fiber contraction for the slow isoform MYH7. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002897332 SUPPORTS TRANSFER Skeletal sarcomeric myosin node seeded by MYH2 itself and its skeletal paralogs; the transfer is valid, but for this fast-fibre isoform the fast-twitch contraction term is supported. Proposed replacements: fast-twitch skeletal muscle fiber contraction Supporting Evidence: PMID:22918376 MyHC IIa (MYH2) is expressed in fast, type 2A muscle fibers PMID:20418530 Striated muscle myosin heavy chain is a molecular motor protein that converts chemical energy into mechanical force. PMID:37788100 Myosin heavy chains encoded by MYH7 and MYH2 are abundant in human skeletal muscle and important for muscle contraction. |
| GO:0006936 muscle contraction | IDA PMID:8145163 Maximum velocity of shortening in relation to myosin isoform... | MODIFY | Summary: Maximum shortening velocity of single human skeletal fibres related to their myosin heavy chain isoform composition, including fibres containing only type IIA MHC. Reason: The study measured mechanics of single soleus and vastus lateralis fibres typed by MHC isoform, including pure type IIA fibres, and relates shortening velocity to MHC composition. This supports MyHC-IIa driving the contraction of fast type 2A fibres; the specific descendant fast-twitch skeletal muscle fiber contraction is supported. The cached record is abstract-only (truncated), so the curator's fuller reading is deferred to for the direction of the conclusion. Proposed replacements: fast-twitch skeletal muscle fiber contraction Supporting Evidence: PMID:8145163 Maximum velocity of shortening (Vmax) and compositions of myosin heavy chain (MHC) and myosin light chain (MLC) isoforms were determined in single fibres from the soleus or the lateral region of the quadriceps (vastus lateralis) muscles in man PMID:8145163 fibres containing type I MHC, types I and IIA MHCs, type IIA MHC, types IIA and IIB MHCs, and type IIB MHC |
| GO:0006936 muscle contraction | TAS PMID:10388558 Comparative sequence analysis of the complete human sarcomer... | MODIFY | Summary: Muscle contraction, traceable to the comparative sequence analysis of the human sarcomeric myosin heavy chain family. Reason: Correct but general; MyHC-IIa drives contraction of fast type 2A skeletal fibres, so the specific descendant fast-twitch skeletal muscle fiber contraction is supported. Proposed replacements: fast-twitch skeletal muscle fiber contraction Supporting Evidence: PMID:10388558 The conventional myosin motor proteins that drive mammalian skeletal and cardiac muscle contraction include eight sarcomeric myosin heavy chain (MyHC) isoforms. PMID:22918376 MyHC IIa (MYH2) is expressed in fast, type 2A muscle fibers |
| GO:0016459 myosin complex | IEA GO_REF:0000002 | MODIFY | Summary: Myosin complex from InterPro domain mapping. Reason: Correct but general; MYH2 is the heavy chain of the hexameric muscle myosin, so the descendant muscle myosin complex (already carried from NAS and TAS rows) is the specific term. Proposed replacements: muscle myosin complex Supporting Evidence: file:human/MYH2/MYH2-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 (MYH2 is a class II myosin heavy chain) but the muscle-specific child term muscle myosin complex, already carried from NAS and 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; MYH2 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/MYH2/MYH2-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 | IEA GO_REF:0000117 | MODIFY | Summary: Myosin II complex from an ARBA rule. Reason: Correct but general; replace with muscle myosin complex. Proposed replacements: muscle myosin complex Supporting Evidence: file:human/MYH2/MYH2-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 | IDA PMID:8145163 Maximum velocity of shortening in relation to myosin isoform... | MODIFY | Summary: Myofibril, from SDS-PAGE identification of type IIA MHC in skinned single fibres of human skeletal muscle. Reason: MyHC-IIa is a myofibrillar protein of skinned fibres, so myofibril is correct but general. MYH2 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band of fast type 2A fibres (UniProt: 'Thick filaments of the myofibrils'). GO:0005863 striated muscle myosin thick filament is the specific supported location, as for MYH7. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: PMID:8145163 Types I, IIA and IIB MHCs were resolved from single fibre segments file:human/MYH2/MYH2-uniprot.txt Note=Thick filaments of the myofibrils. PMID:37788100 Immunofluorescence staining of both patient and control myofibers expressing either Ξ²/slow or type IIA MHC showed that muscle sarcomeres were well preserved, as indicated by regular striated arrays of myosin filaments |
| GO:0030016 myofibril | IEA GO_REF:0000044 | MODIFY | Summary: Myofibril from UniProt subcellular-location mapping. Reason: Correct but general. MYH2 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band of fast type 2A fibres (UniProt: 'Thick filaments of the myofibrils'). GO:0005863 striated muscle myosin thick filament is the specific supported location. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: file:human/MYH2/MYH2-uniprot.txt Note=Thick filaments of the myofibrils. PMID:22918376 The myosin heavy chain (MyHC) is the molecular motor of muscle and forms the backbone of the sarcomere thick filaments. |
| GO:0030017 sarcomere | NAS PMID:3904738 The myosin alkali light chain proteins and their genes. | MODIFY | Summary: Sarcomere, by author statement in a 1985 review of myosin alkali light chains. Reason: Correct but general. MYH2 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band of fast type 2A fibres (UniProt: 'Thick filaments of the myofibrils'). GO:0005863 striated muscle myosin thick filament (part_of sarcomere) is the specific supported location. The cached record has no abstract, so the curator's source statement could not be read. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: file:human/MYH2/MYH2-uniprot.txt Note=Thick filaments of the myofibrils. PMID:22918376 The myosin heavy chain (MyHC) is the molecular motor of muscle and forms the backbone of the sarcomere thick filaments. |
| GO:0030049 muscle filament sliding | NAS PMID:3904738 The myosin alkali light chain proteins and their genes. | ACCEPT | Summary: Muscle filament sliding, by author statement in a 1985 review of myosin alkali light chains. Reason: The MyHC-IIa heads cyclically bind actin thin filaments and pull them past the thick filament; filament sliding is the process MYH2 executes directly in fast type 2A fibres. Recombinant MyHC-IIa moves actin filaments in vitro, and the E706K motor-domain variant severely impairs IIa motor function in single-fibre motility assays. The cached record has no abstract, but the assertion matches direct evidence. Supporting Evidence: PMID:20080549 Our data also show that ATPase activity and motility are generally correlated for human skeletal muscle myosins. PMID:17005402 Contractile properties were measured in single muscle fiber segments using the skinned fiber preparation and a single muscle fiber in vitro motility assay. PMID:17005402 A dramatic impairment in the function of the IIa MyHC isoform was observed at the motor protein level. |
| 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. MYH2 light meromyosin packs into filaments, and MYH2 LMM myopathy variants alter coiled-coil structure and filament packing; in muscle these are the bipolar thick filaments of the sarcomere A band. GO:0005863 striated muscle myosin thick filament (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; MYH2 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:37788100 The MYH2 proline mutant (L1870P) did form filaments from homogeneous mixtures, which were shorter and narrower than WT file:human/MYH2/MYH2-uniprot.txt Note=Thick filaments of the myofibrils. |
| GO:0032991 protein-containing complex | IDA GO_REF:0000054 | MODIFY | Summary: Protein-containing complex, from a large-scale localization study of expressed fusion proteins in living cells. Reason: The term is correct but less specific than the evidence supports. MYH2 is a subunit of the hexameric muscle myosin, so the row is refined to muscle myosin complex (GO:0005859), the same replacement used for the myosin complex and myosin II complex rows in this review. Proposed replacements: muscle myosin complex Supporting Evidence: file:human/MYH2/MYH2-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:0043292 contractile muscle fiber | IEA GO_REF:0000117 | MODIFY | Summary: Contractile muscle fiber (the myofibril-level structure), from an ARBA rule. Reason: Correct but general. MYH2 assembles via its light meromyosin rod into the bipolar thick filaments of the sarcomere A band of fast type 2A fibres (UniProt: 'Thick filaments of the myofibrils'). GO:0005863 striated muscle myosin thick filament is the specific supported location. Proposed replacements: striated muscle myosin thick filament Supporting Evidence: file:human/MYH2/MYH2-uniprot.txt Note=Thick filaments of the myofibrils. |
| 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 661-683 and 763-777); strong actin binding is a step of every cross-bridge cycle, and the actin affinity of the ADP-bound head (K_AD) is the kinetic property that best distinguishes MyHC-IIa from the other fast isoforms. Supporting Evidence: PMID:23908353 the affinity of ADP for actinΒ·myosin (K(AD)) is the characteristic that most readily distinguishes the isoforms PMID:23908353 The three fast muscle myosins have K(AD) values of 118, 80, and 55 PMID:36745529 Overall, our findings indicate that MYH2 truncating mutations impact myosin presence/functionality in human adult mature myofibers by disrupting the ATPase activity and actomyosin complex. |
| 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:23908353 the affinity of ADP for actinΒ·myosin (K(AD)) is the characteristic that most readily distinguishes the isoforms |
| GO:0008307 structural constituent of muscle | IDA PMID:37788100 Human skeletal myopathy myosin mutations disrupt myosin head... | NEW | Summary: The MYH2 rod (light meromyosin) is a building block of the thick filament backbone of fast type 2A fibres; expressed MYH2 LMM forms filaments in vitro, and a myopathy variant (L1870P) reduces helical content and yields shorter, narrower filaments. Reason: Besides its motor activity, MYH2 is a principal structural component of the thick filaments of fast type 2A fibres: its light meromyosin self-assembles into filaments, and MYH2 LMM myopathy variants disrupt coiled-coil structure and filament packing. Comparator check (QuickGO): other muscle myosin heavy chains 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 follows an established convention for muscle myosins. Supporting Evidence: PMID:37788100 Analyses of expressed and purified MYH7 and MYH2 LMM mutant proteins combined with in silico modeling showed that myosin coiled coil structure and packing of filaments in vitro are commonly disrupted. PMID:37788100 The MYH2 proline mutant (L1870P) did form filaments from homogeneous mixtures, which were shorter and narrower than WT PMID:22918376 The myosin heavy chain (MyHC) is the molecular motor of muscle and forms the backbone of the sarcomere thick filaments. file:human/MYH2/MYH2-uniprot.txt Note=Thick filaments of the myofibrils. |
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Download this section (compressed HTML)Q: Should the cell-cell junction annotation from PMID:25753039, which describes endothelial non-muscle myosin IIA, be transferred from MYH2 to MYH9? The shared name 'myosin IIA/IIa' appears to have caused the mis-mapping, and the same check may be worth running on other annotations citing 'myosin IIA'.
Suggested experts: GOA curators
Q: GO has no term for the regulated sequestration of myosin heads in the interacting-heads motif / super-relaxed state. MYH2 light meromyosin variants reduce this state in patient type IIA fibres without lowering force. Should a term be created so that this property of skeletal as well as cardiac class II myosins can be annotated?
Suggested experts: GO editors, muscle myosin biophysicists
Q: Why does loss of MyHC-IIa, an isoform of limb type 2A fibres, so consistently produce external ophthalmoplegia? Which extraocular muscle fibre populations depend on MyHC-IIa, and is the effect developmental or contractile?
Suggested experts: neuromuscular geneticists, extraocular muscle physiologists
Experiment: Express full-length human MYH2 carrying E706K, S2 rod and LMM variants in human myotubes and measure thick-filament incorporation, mant-ATP single-turnover (super-relaxed state fraction) and in vitro motility of the purified mutant myosin, compared with wild type.
Hypothesis: Motor-domain variants impair the power stroke, whereas rod variants act mainly by disrupting filament packing and head sequestration, raising basal ATP turnover.
Type: cell-based assembly assays and biochemistry of recombinant myosin
Experiment: Characterize MyHC isoform composition and contractile properties of single extraocular muscle fibres from patients with recessive MYH2 null variants and from controls.
Hypothesis: A population of extraocular fibres relies on MyHC-IIa and cannot compensate with other isoforms.
Type: single-fibre proteomics and mechanics
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