MYL2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0002026 regulation of the force of heart contraction	ISS GO_REF:0000024	MODIFY	Summary: ISS transfer from rat Myl2 (P08733) of a role in regulating the force of heart contraction. In mammalian myocardium MLCK-catalysed phosphorylation of the ventricular RLC raises the calcium sensitivity of isometric force and the maximal force, so MYL2 is the phospho-switch subunit through which force is tuned. Reason: The claim is correct but less specific than the evidence: the direction of the effect is known (phosphorylated RLC increases force and calcium sensitivity), and the gene already carries the descendant GO:0098735 positive regulation of the force of heart contraction. The evidence is from mouse myocardium (same PANTHER subfamily PTHR23049:SF9 one-to-one ortholog); there is no equivalent human in-situ force measurement in the cited set, although human cardiac-MLCK phosphorylates MLC2v. Proposed replacements: positive regulation of the force of heart contraction Supporting Evidence: PMID:16908724 MLCK increased RLC phosphorylation, increased the Ca(2+) sensitivity of isometric force PMID:10409661 Ca(2+) sensitivity of force development was dependent upon the phosphorylation status of the regulatory light chain PMID:17885681 cardiac-specific myosin light chain kinase (cardiac-MLCK), which acts on MLC2v
GO:0003785 actin monomer binding	IDA PMID:9180271 Different actin affinities of human cardiac essential myosin...	UNDECIDED	Summary: IDA for actin monomer binding citing Morano and Haase 1997. The abstract describes peptides from the N terminus of the essential light chains (MLC-1; ALC-1/MYL4 and VLC-1/MYL3) competing for G-actin binding. MYL2 is the regulatory light chain and is not named among the tested peptides. Reason: The cached record is abstract-only and the abstract explicitly states that the assayed peptides were the N-terminal sequences of the human cardiac essential light chains ALC-1 and VLC-1, which carry the actin-binding N-terminal extension that RLCs lack. The annotation may reflect confusion between 'ventricular light chain 1' (MYL3) and MLC-2v (MYL2), but the full text has not been read, so it is left UNDECIDED rather than removed. No other source in this review shows MYL2 binding actin monomers; RLC binds the heavy-chain neck. Supporting Evidence: PMID:9180271 These results demonstrate the specific interaction between the N-terminal domains of human cardiac MLC-1 isoforms and actin
GO:0005509 calcium ion binding	IBA GO_REF:0000033	ACCEPT	Summary: MYL2 has a canonical calcium-coordinating loop in its first EF hand (UniProt binding sites D37, D39, D41, D48). Recombinant human MYL2 binds Ca2+ with a measurable affinity that is changed by HCM mutations and by Ser15 phosphorylation (Szczesna et al. 2001). The site is the Ca2+/Mg2+ site typical of regulatory light chains. This IBA comes from PAINT node PTN000549442 (sarcomeric RLCs: MYL2, MYL7, MYLPF, MYL10), for which MYL2 itself is the experimental donor. Reason: Direct human biochemical evidence (IDA on this gene) plus conserved EF-hand loop; the IBA correctly records that this property is inherited across the sarcomeric RLC clade. MYL2 appearing in its own WITH/FROM is the expected grounding, not circularity. Calcium binding is a supporting property; its physiological role at the RLC site (Mg2+ occupied at rest) is not fully resolved. Supporting Evidence: PMID:11102452 the R58Q mutant did not bind Ca(2+) PMID:11102452 Whereas phosphorylation of wild-type light chain decreased its Ca(2+) affinity file:human/MYL2/MYL2-uniprot.txt MISCELLANEOUS: This chain binds calcium.
GO:0005509 calcium ion binding	IDA PMID:11102452 Familial hypertrophic cardiomyopathy mutations in the regula...	ACCEPT	Summary: MYL2 has a canonical calcium-coordinating loop in its first EF hand (UniProt binding sites D37, D39, D41, D48). Recombinant human MYL2 binds Ca2+ with a measurable affinity that is changed by HCM mutations and by Ser15 phosphorylation (Szczesna et al. 2001). The site is the Ca2+/Mg2+ site typical of regulatory light chains. Reason: Szczesna et al. measured Ca2+ binding (K_Ca) of recombinant wild-type and mutant human ventricular RLC, which is direct evidence for this gene product. Supporting Evidence: PMID:11102452 the R58Q mutant did not bind Ca(2+) PMID:11102452 Whereas phosphorylation of wild-type light chain decreased its Ca(2+) affinity
GO:0005509 calcium ion binding	IEA GO_REF:0000002	ACCEPT	Summary: MYL2 has a canonical calcium-coordinating loop in its first EF hand (UniProt binding sites D37, D39, D41, D48). Recombinant human MYL2 binds Ca2+ with a measurable affinity that is changed by HCM mutations and by Ser15 phosphorylation (Szczesna et al. 2001). The site is the Ca2+/Mg2+ site typical of regulatory light chains. IEA from the InterPro EF-hand domain mapping. Reason: Consistent with the human IDA and the IBA; the first EF-hand loop is intact. Supporting Evidence: PMID:11102452 the R58Q mutant did not bind Ca(2+) file:human/MYL2/MYL2-uniprot.txt /ligand="Ca(2+)"
GO:0005515 protein binding	IPI PMID:11773029 Protein interactions with myocilin.	REMOVE	Summary: IPI with myocilin (MYOC) from a yeast two-hybrid screen of a skeletal muscle library, confirmed by co-immunoprecipitation in trabecular meshwork cells. Reason: Generic protein binding is uninformative under the repository protein-binding policy; removal does not dispute that the interaction was observed. The interaction is with a secreted/ER glaucoma protein in trabecular meshwork cells; it does not establish a molecular function of MYL2 in muscle and no more specific MF term is justified. Supporting Evidence: PMID:11773029 Myocilin was also found to interact with a component of the myosin motor protein, myosin regulatory light chain (RLC).
GO:0005515 protein binding	IPI PMID:16555005 The Tre2 oncoprotein, implicated in Ewing's sarcoma, interac...	REMOVE	Summary: IPI with the GAP region of the Tre2/USP6 oncoprotein, from yeast two-hybrid and GST pull-down. Reason: Generic protein binding is uninformative under the repository protein-binding policy; removal does not dispute that the interaction was observed. The abstract calls the partner 'the light regulatory chain of myosin II (Myl2)'; the screened libraries and cell types are not muscle, so the identity of the RLC paralog engaged in vivo is uncertain, and no specific MF follows from the observation. Supporting Evidence: PMID:16555005 The proteins found to interact with the GAP region are the light regulatory chain of myosin II (Myl2)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Binary interaction with IRX6 from the HuRI systematic yeast two-hybrid map. Reason: Generic protein binding is uninformative under the repository protein-binding policy; removal does not dispute that the interaction was observed. A homeobox transcription factor partner from a systematic screen has no known relevance to MYL2's sarcomeric role.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Binary interaction with PSORS1C2 from the HuRI systematic yeast two-hybrid map. Reason: Generic protein binding is uninformative under the repository protein-binding policy; removal does not dispute that the interaction was observed. No functional context links PSORS1C2 to MYL2.
GO:0005737 cytoplasm	IBA GO_REF:0000033	MODIFY	Summary: Deep-node IBA (PTN001495767, spanning RLC-family members from fungi to animals) placing the light chain in the cytoplasm. Reason: True but general. MYL2 is incorporated into myosin thick filaments in the A band of the sarcomere; the gene already carries GO:0031672 A band, a part_of descendant of cytoplasm, which is the informative location. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001495767 SUPPORTS TRANSFER Deep RLC/light-chain ancestor carrying a generic cytoplasm IBD; correct for MYL2, but the informative location (A band) is already asserted. Proposed replacements: A band Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere, A band PMID:8287067 binds with specificity to MHC and to intact myofibrils
GO:0005829 cytosol	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Cytosol from an ARBA machine-learning rule. Reason: MYL2 is a subunit of sarcomeric myosin and is found assembled in thick filaments of the myofibril, not as a free cytosolic protein. Reactome places its muscle-contraction reactions in the cytosol by compartment convention, and the ARBA rule is a generic prediction. The term is not strictly wrong (sarcomeric myosin is not membrane-bounded) but it misrepresents where the protein acts. Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere, A band
GO:0005829 cytosol	TAS Reactome:R-HSA-390593	MARK AS OVER ANNOTATED	Summary: Cytosol from the Reactome striated-muscle contraction reaction Reactome:R-HSA-390593, in which MYL2 participates as a myosin light chain. Reason: MYL2 is a subunit of sarcomeric myosin and is found assembled in thick filaments of the myofibril, not as a free cytosolic protein. Reactome places its muscle-contraction reactions in the cytosol by compartment convention, and the ARBA rule is a generic prediction. The term is not strictly wrong (sarcomeric myosin is not membrane-bounded) but it misrepresents where the protein acts. Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere, A band
GO:0005829 cytosol	TAS Reactome:R-HSA-390595	MARK AS OVER ANNOTATED	Summary: Cytosol from the Reactome striated-muscle contraction reaction Reactome:R-HSA-390595, in which MYL2 participates as a myosin light chain. Reason: MYL2 is a subunit of sarcomeric myosin and is found assembled in thick filaments of the myofibril, not as a free cytosolic protein. Reactome places its muscle-contraction reactions in the cytosol by compartment convention, and the ARBA rule is a generic prediction. The term is not strictly wrong (sarcomeric myosin is not membrane-bounded) but it misrepresents where the protein acts. Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere, A band
GO:0005829 cytosol	TAS Reactome:R-HSA-390597	MARK AS OVER ANNOTATED	Summary: Cytosol from the Reactome striated-muscle contraction reaction Reactome:R-HSA-390597, in which MYL2 participates as a myosin light chain. Reason: MYL2 is a subunit of sarcomeric myosin and is found assembled in thick filaments of the myofibril, not as a free cytosolic protein. Reactome places its muscle-contraction reactions in the cytosol by compartment convention, and the ARBA rule is a generic prediction. The term is not strictly wrong (sarcomeric myosin is not membrane-bounded) but it misrepresents where the protein acts. Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere, A band
GO:0005829 cytosol	TAS Reactome:R-HSA-390598	MARK AS OVER ANNOTATED	Summary: Cytosol from the Reactome striated-muscle contraction reaction Reactome:R-HSA-390598, in which MYL2 participates as a myosin light chain. Reason: MYL2 is a subunit of sarcomeric myosin and is found assembled in thick filaments of the myofibril, not as a free cytosolic protein. Reactome places its muscle-contraction reactions in the cytosol by compartment convention, and the ARBA rule is a generic prediction. The term is not strictly wrong (sarcomeric myosin is not membrane-bounded) but it misrepresents where the protein acts. Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere, A band
GO:0005856 cytoskeleton	IDA PMID:17043135 Endosomes generate localized Rho-ROCK-MLC2-based contractile...	MODIFY	Summary: IDA for cytoskeleton from a study of Endo180-driven Rho-ROCK contractility in MG63 osteosarcoma and other non-muscle cells. Staining used antibodies against MLC2 phosphorylated at Thr18/Ser19, the ROCK/MLCK sites of nonmuscle and smooth-muscle RLCs. Reason: The review judges the claim, and the claim is true of MYL2: as a light chain of muscle myosin it is part of the muscle myosin complex (GO:0005859), which GO places under actin cytoskeleton and cytoskeleton, and GFP-MYL2 decorates the cytoskeleton of H9c2 cardiomyoblasts. The cited evidence, however, does not appear to concern MYL2. I read the full text: staining used antibodies to MLC2 phosphorylated at Thr18/Ser19, the ROCK/MLCK sites of the nonmuscle and smooth-muscle RLCs (MYL9/MYL12A/MYL12B), in MG63 osteosarcoma and other non-muscle cells. MYL2's regulatory site is Ser15. The replacement term is therefore supported by other sources, and this row's reference should be reassigned to the nonmuscle RLC genes. Proposed replacements: muscle myosin complex Supporting Evidence: PMID:17043135 Rabbit anti–human monophospho-MLC2 (Ser19) and diphospho-MLC2 (Thr18/Ser19) PMID:32453731 which showed strong localization along the cell cytoskeleton PMID:8673105 The light chains stabilize the long alpha helical neck of the myosin head.
GO:0005856 cytoskeleton	TAS PMID:8673105 Mutations in either the essential or regulatory light chains...	MODIFY	Summary: TAS for cytoskeleton from Poetter et al. 1996, which describes the RLC as a component of the myosin hexamer stabilising the heavy-chain neck. Reason: Correct but general: as a myosin light chain MYL2 is part of the muscle myosin complex (GO:0005859), which GO places under actin cytoskeleton and cytoskeleton, and the gene already carries that term. GFP-MYL2 also decorates the cytoskeleton of H9c2 cardiomyoblasts. Proposed replacements: muscle myosin complex Supporting Evidence: PMID:8673105 The light chains stabilize the long alpha helical neck of the myosin head. PMID:32453731 which showed strong localization along the cell cytoskeleton
GO:0005859 muscle myosin complex	NAS PMID:16563742 Structure and function of myosin filaments.	ACCEPT	Summary: NAS from a review of myosin filament structure; MYL2 is the regulatory light chain of the beta-cardiac/slow skeletal myosin II hexamer. Reason: Core location. Recombinant human MYL2 exchanges into native myosin and binds the heavy chain and myofibrils, and loss of MYL2 cannot be compensated by MLC2a in ventricular sarcomere assembly. Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt Myosin is a hexamer of 2 heavy chains and 4 light chains. PMID:8287067 binds with specificity to MHC and to intact myofibrils PMID:8673105 The light chains stabilize the long alpha helical neck of the myosin head.
GO:0006942 regulation of striated muscle contraction	TAS PMID:8673105 Mutations in either the essential or regulatory light chains...	ACCEPT	Summary: TAS that MYL2 regulates striated muscle contraction; Poetter et al. proposed that RLC mutations disrupt the stretch-activation response of cardiac papillary muscle. Reason: MYL2 is expressed in ventricular and slow skeletal muscle and its phosphorylation modulates calcium sensitivity, force and stretch activation, so this level spans both muscle types. The mechanistic data are from mouse myocardium (orthologous, same PANTHER subfamily SF9) and the human genetic data are consistent with them. Supporting Evidence: PMID:8673105 The light chains stabilize the long alpha helical neck of the myosin head. PMID:16908724 MLCK increased RLC phosphorylation, increased the Ca(2+) sensitivity of isometric force PMID:16908724 MLCK had profound effects on the stretch activation responses
GO:0007507 heart development	IBA GO_REF:0000033	MODIFY	Summary: IBA from MYL2-branch node PTN002746142 (donors mouse Myl2, rat Myl2 and human MYL2). Reason: Heart development is true but general; the contribution MYL2 itself makes is structural, to the assembly of ventricular sarcomeres (mouse Myl2-null embryos die about E12.5 with defective sarcomeric assembly even though MLC2a replaces it). Chamber morphology and lethality are downstream consequences. The gene already carries GO:0055003 cardiac myofibril assembly, a part_of descendant of heart development, which states what MYL2 does. Evidence is from mouse (same PANTHER subfamily, one-to-one ortholog); human recessive MYL2 loss causes infantile cardiomyopathy with myofibrillar disorganization, which is consistent. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002746142 SUPPORTS TRANSFER MYL2-branch node; MYL2 is inside the clade and the mouse knockout grounds the assertion, but the specific contribution is cardiac myofibril assembly. Proposed replacements: cardiac myofibril assembly Supporting Evidence: PMID:9422794 ultrastructural analysis revealed defects in sarcomeric assembly PMID:9422794 despite the substitution of myosin light chain 2a
GO:0007507 heart development	IEA GO_REF:0000107	MODIFY	Summary: Ensembl Compara transfer from mouse Myl2. Reason: Heart development is true but general; the contribution MYL2 itself makes is structural, to the assembly of ventricular sarcomeres (mouse Myl2-null embryos die about E12.5 with defective sarcomeric assembly even though MLC2a replaces it). Chamber morphology and lethality are downstream consequences. The gene already carries GO:0055003 cardiac myofibril assembly, a part_of descendant of heart development, which states what MYL2 does. Evidence is from mouse (same PANTHER subfamily, one-to-one ortholog); human recessive MYL2 loss causes infantile cardiomyopathy with myofibrillar disorganization, which is consistent. Proposed replacements: cardiac myofibril assembly Supporting Evidence: PMID:9422794 ultrastructural analysis revealed defects in sarcomeric assembly
GO:0007507 heart development	ISS GO_REF:0000024	MODIFY	Summary: ISS transfer from mouse Myl2 (P51667). Reason: Heart development is true but general; the contribution MYL2 itself makes is structural, to the assembly of ventricular sarcomeres (mouse Myl2-null embryos die about E12.5 with defective sarcomeric assembly even though MLC2a replaces it). Chamber morphology and lethality are downstream consequences. The gene already carries GO:0055003 cardiac myofibril assembly, a part_of descendant of heart development, which states what MYL2 does. Evidence is from mouse (same PANTHER subfamily, one-to-one ortholog); human recessive MYL2 loss causes infantile cardiomyopathy with myofibrillar disorganization, which is consistent. Proposed replacements: cardiac myofibril assembly Supporting Evidence: PMID:9422794 ultrastructural analysis revealed defects in sarcomeric assembly
GO:0008307 structural constituent of muscle	IMP PMID:23365102 Recessive MYL2 mutations cause infantile type I muscle fibre...	ACCEPT	Summary: MYL2 is a structural subunit of the cardiac/slow-skeletal myosin hexamer that wraps and stiffens the heavy-chain lever arm. Recessive C-terminal MYL2 mutations cause a lethal infantile myopathy and cardiomyopathy with type I fibre hypotrophy and myofibrillar disorganization (human genetics). Reason: Core function. Human loss-of-function genetics, structural knowledge of the RLC-heavy chain neck interaction and the mouse knockout all support a structural role in the sarcomere. Supporting Evidence: PMID:23365102 have a structural and regulatory role in muscle contraction PMID:8673105 The light chains stabilize the long alpha helical neck of the myosin head.
GO:0008307 structural constituent of muscle	IMP PMID:32453731 Novel frameshift variant in MYL2 reveals molecular differenc...	ACCEPT	Summary: MYL2 is a structural subunit of the cardiac/slow-skeletal myosin hexamer that wraps and stiffens the heavy-chain lever arm. A homozygous frameshift abolishing MYL2 protein causes infantile HCM; wild-type human MYL2, but not the frameshift or G162R variant, partially rescues heart function after knockdown of Drosophila Mlc2. Reason: Core function, supported by human genetics and a cross-species rescue with the human protein. Supporting Evidence: PMID:32453731 was partially rescued by the wildtype human MYL2 overexpression PMID:32453731 which showed strong localization along the cell cytoskeleton
GO:0008307 structural constituent of muscle	NAS PMID:17885681 A cardiac myosin light chain kinase regulates sarcomere asse...	ACCEPT	Summary: MYL2 is a structural subunit of the cardiac/slow-skeletal myosin hexamer that wraps and stiffens the heavy-chain lever arm. Seguchi et al. describe MLC2v as an important structural protein of the cardiac sarcomere and identify cardiac-MLCK (MYLK3) as its kinase in human heart. Reason: Consistent with the IMP rows; core. Supporting Evidence: PMID:17885681 is an important structural protein that affects physiologic cardiac sarcomere formation and heart development
GO:0008307 structural constituent of muscle	TAS PMID:8673105 Mutations in either the essential or regulatory light chains...	ACCEPT	Summary: MYL2 is a structural subunit of the cardiac/slow-skeletal myosin hexamer that wraps and stiffens the heavy-chain lever arm. Reason: Consistent with the IMP rows; core. Supporting Evidence: PMID:8673105 The light chains stabilize the long alpha helical neck of the myosin head.
GO:0015629 actin cytoskeleton	IDA PMID:17043135 Endosomes generate localized Rho-ROCK-MLC2-based contractile...	UNDECIDED	Summary: IDA colocalizes_with actin cytoskeleton from the Endo180/ROCK study in non-muscle cells (Thr18/Ser19 phospho-MLC2 staining). Reason: As for the cytoskeleton row from the same paper: the full text shows the antibody detected the nonmuscle RLC phospho-epitope in osteosarcoma cells, so this does not appear to be evidence about MYL2. Not removed because sarcomeric myosin containing MYL2 does associate with actin filaments. Supporting Evidence: PMID:17043135 Rabbit anti–human monophospho-MLC2 (Ser19) and diphospho-MLC2 (Thr18/Ser19)
GO:0016459 myosin complex	TAS PMID:11102452 Familial hypertrophic cardiomyopathy mutations in the regula...	MODIFY	Summary: TAS for myosin complex from the Szczesna et al. study of RLC HCM mutants, which characterised MYL2 as a myosin light chain. Reason: Correct but general; MYL2 is specifically a light chain of muscle (class II) myosin, and the gene carries GO:0005859 muscle myosin complex. Proposed replacements: muscle myosin complex Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt Myosin is a hexamer of 2 heavy chains and 4 light chains. PMID:8287067 binds with specificity to MHC and to intact myofibrils
GO:0030016 myofibril	IBA GO_REF:0000033	MODIFY	Summary: IBA (PTN002746142, MYL2 branch) for myofibril. Reason: Myofibril is correct but general. MYL2 is a thick-filament protein; the gene already carries GO:0031672 A band (part_of sarcomere, part_of myofibril). GO:0097512 cardiac myofibril is also accepted for heart; A band is chosen as the replacement because MYL2 is also the slow skeletal muscle RLC. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002746142 SUPPORTS TRANSFER MYL2-branch node; myofibril is correct for the clade, A band is the more specific location already carried. Proposed replacements: A band Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere, A band PMID:8287067 binds with specificity to MHC and to intact myofibrils
GO:0030016 myofibril	IEA GO_REF:0000107	MODIFY	Summary: Ensembl Compara transfer from mouse Myl2 for myofibril. Reason: Myofibril is correct but general. MYL2 is a thick-filament protein; the gene already carries GO:0031672 A band (part_of sarcomere, part_of myofibril). GO:0097512 cardiac myofibril is also accepted for heart; A band is chosen as the replacement because MYL2 is also the slow skeletal muscle RLC. Proposed replacements: A band Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere, A band
GO:0030016 myofibril	NAS PMID:8287067 Interaction of a conserved peptide domain in recombinant hum...	MODIFY	Summary: NAS from Wadgaonkar et al., who showed recombinant human MLC2 binds intact myofibrils. Reason: Myofibril is correct but general. MYL2 is a thick-filament protein; the gene already carries GO:0031672 A band (part_of sarcomere, part_of myofibril). GO:0097512 cardiac myofibril is also accepted for heart; A band is chosen as the replacement because MYL2 is also the slow skeletal muscle RLC. Proposed replacements: A band Supporting Evidence: PMID:8287067 binds with specificity to MHC and to intact myofibrils
GO:0030017 sarcomere	NAS PMID:16563742 Structure and function of myosin filaments.	MODIFY	Summary: NAS from a review of myosin filament structure. Reason: Sarcomere is correct but general; MYL2 is restricted to the thick-filament A band, which the gene already carries (GO:0031672). Proposed replacements: A band Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere, A band
GO:0030017 sarcomere	TAS PMID:16754800 Single-gene mutations and increased left ventricular wall th...	MODIFY	Summary: TAS from the Framingham study of sarcomere-gene mutations in increased left-ventricular wall thickness, which includes MYL2 among sequenced sarcomere protein genes. Reason: Sarcomere is correct but general; MYL2 is restricted to the thick-filament A band, which the gene already carries (GO:0031672). The cited population-genetics paper says nothing about subcellular location beyond grouping MYL2 with sarcomere genes, so it is weak support; the location itself is well established. Proposed replacements: A band Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere, A band
GO:0030048 actin filament-based movement	NAS PMID:10722873 Myosins: a diverse superfamily.	MODIFY	Summary: NAS from a review of the myosin superfamily (focused on unconventional myosins and nonmuscle myosin II). Reason: MYL2 does take part in actin filament-based movement as the lever-arm light chain of sarcomeric myosin, but the specific process is muscle filament sliding (GO:0030049, is_a actin-myosin filament sliding, part_of muscle contraction). The cited review is about other myosins and is weak support for MYL2. Proposed replacements: muscle filament sliding Supporting Evidence: PMID:8673105 The light chains stabilize the long alpha helical neck of the myosin head. PMID:23365102 have a structural and regulatory role in muscle contraction
GO:0030308 negative regulation of cell growth	IMP PMID:15824735 Identification of novel VHL target genes and relationship to...	MARK AS OVER ANNOTATED	Summary: IMP/overexpression: re-expression of 'MLC2' (identified as a pVHL-upregulated transcript) in a renal cell carcinoma line suppressed tumour cell growth. Reason: Abstract-only. The result comes from ectopic expression of a sarcomeric light chain in a kidney tumour line; it is not a physiological growth-regulatory function of MYL2 and has no support from muscle biology. Not removed because the full text (and which RLC transcript was used) has not been verified. Supporting Evidence: PMID:15824735 MLC2 (myosin light chain) in a RCC cell line suppressed tumour cell growth
GO:0031672 A band	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular location mapping: cytoplasm, myofibril, sarcomere, A band. Reason: Core location: MYL2 is a thick-filament myosin light chain, and thick filaments define the A band. The UniProt statement is by similarity to rat, consistent with human MYL2 binding myofibrils and the myosin heavy chain. Supporting Evidence: file:human/MYL2/MYL2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, myofibril, sarcomere, A band PMID:8287067 binds with specificity to MHC and to intact myofibrils
GO:0032036 myosin heavy chain binding	NAS PMID:8287067 Interaction of a conserved peptide domain in recombinant hum...	MODIFY	Summary: Recombinant human ventricular MLC2 exchanges into native myosin and binds the myosin heavy chain and subfragment-1 through a conserved central domain (Wadgaonkar et al. 1993). Curated as NAS. Reason: The binding is direct and experimentally shown for the human protein, so the claim is sound; the partner is the class II (beta-cardiac) myosin heavy chain, so the more specific GO:0032038 myosin II heavy chain binding applies. This is the core molecular interaction by which MYL2 contributes to the motor. Proposed replacements: myosin II heavy chain binding Supporting Evidence: PMID:8287067 binds with specificity to MHC and to intact myofibrils PMID:8287067 a conserved central domain in MLC2 participates in the functional association
GO:0042694 muscle cell fate specification	IBA GO_REF:0000033	REMOVE	Summary: IBA from MYL2-branch node PTN002746142; the only donor is mouse Myl2 with an IMP from Lee et al. 1992, a promoter-luciferase transgenic study of MLC-2 gene regulation. Reason: Muscle cell fate specification would require MYL2 to help commit cells to a muscle fate. MYL2 is a terminal differentiation product and a classic ventricular marker gene. The donor paper studied cis-regulatory elements that control MLC-2 expression, which concerns the regulation of MYL2 rather than a function of the MYL2 protein. Nothing in the gene's biology supports a fate-specification role, so the propagated assertion is rejected on biological grounds. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002746142 SOURCE BAD MYL2-branch node whose fate-specification IBD rests on a single mouse donor annotation from a promoter-reporter study. MGI:MGI:97272 SOURCE BAD Mouse Myl2 IMP (PMID:1379240) studies cis-regulation of MLC-2 expression, i.e. MYL2 as a differentiation marker, not as an agent of muscle fate specification. Supporting Evidence: PMID:1379240 both the endogenous MLC-2 gene and the MLC-2 luciferase fusion gene were expressed exclusively in the ventricular compartment
GO:0055003 cardiac myofibril assembly	ISS GO_REF:0000024	ACCEPT	Summary: ISS from mouse Myl2: Myl2-null embryos have defective ventricular sarcomere assembly despite compensatory upregulation and incorporation of MLC2a. Reason: MYL2 contributes structurally to the myofibrils it assembles into, which is participation and not merely necessity, and the defect is specific to the MLC2v protein because MLC2a cannot substitute. The evidence is from mouse (one-to-one ortholog, PANTHER SF9). Human recessive loss-of-function causes myofibrillar disorganization, which is consistent. Not experimentally shown in human cells. Supporting Evidence: PMID:9422794 ultrastructural analysis revealed defects in sarcomeric assembly PMID:9422794 despite the substitution of myosin light chain 2a PMID:17885681 is an important structural protein that affects physiologic cardiac sarcomere formation and heart development
GO:0055010 ventricular cardiac muscle tissue morphogenesis	IMP PMID:8673105 Mutations in either the essential or regulatory light chains...	MARK AS OVER ANNOTATED	Summary: IMP for ventricular cardiac muscle tissue morphogenesis from Poetter et al. 1996, the identification of RLC missense mutations in a rare hypertrophic cardiomyopathy with mid-ventricular obstruction. Reason: Hypertrophy in patients carrying dominant MYL2 missense mutations is a downstream organismal phenotype of altered myosin function, not evidence that MYL2 carries out morphogenesis of ventricular tissue. MYL2's own contribution is captured by cardiac myofibril assembly and cardiac muscle contraction. Not removed, because the curator read the full text and the gene is plainly required for normal ventricular development. Supporting Evidence: PMID:8673105 The light chains stabilize the long alpha helical neck of the myosin head.
GO:0060047 heart contraction	ISS GO_REF:0000024	MODIFY	Summary: ISS from mouse Myl2 for heart contraction. Reason: Correct but general; MYL2 acts within the cardiomyocyte contractile apparatus, and the gene carries the specific term GO:0060048 cardiac muscle contraction (part_of heart contraction). Proposed replacements: cardiac muscle contraction Supporting Evidence: PMID:16908724 MLCK increased RLC phosphorylation, increased the Ca(2+) sensitivity of isometric force PMID:32453731 was partially rescued by the wildtype human MYL2 overexpression
GO:0060048 cardiac muscle contraction	IBA GO_REF:0000033	ACCEPT	Summary: IBA from PTN002746142 (MYL2 branch; mouse and rat Myl2 donors). Reason: Core process. MYL2 is a subunit of the ventricular myosin motor, its phosphorylation tunes force development, and wild-type human MYL2 restores cardiac fractional shortening in Drosophila Mlc2-knockdown hearts. The node placement on the MYL2 branch is appropriate. Supporting Evidence: PMID:16908724 MLCK increased RLC phosphorylation, increased the Ca(2+) sensitivity of isometric force PMID:32453731 was partially rescued by the wildtype human MYL2 overexpression
GO:0097512 cardiac myofibril	IDA PMID:25771144 A novel phosphorylation site, Serine 199, in the C-terminus ...	ACCEPT	Summary: IDA for cardiac myofibril from Wijnker et al. 2015, in which MYL2 was quantified as a myofilament protein in human donor and failing cardiac tissue and skinned cardiomyocytes. Reason: Human cardiac tissue evidence that MYL2 is a myofibrillar protein; consistent with A band localization. Supporting Evidence: PMID:25771144 normalized to the intensities of the SYPRO Ruby stained myosin light chain 2 bands
GO:0098735 positive regulation of the force of heart contraction	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara transfer from mouse Myl2 (IDA, Stelzer et al. 2006). Reason: MLCK phosphorylation of the ventricular RLC increases calcium sensitivity, Ca2+-activated force and stretch-activation kinetics in mouse myocardium, and mice with nonphosphorylatable MLC2v have reduced calcium sensitivity and cardiac dysfunction. MYL2 is the protein whose phosphorylation carries this regulatory effect. Mouse evidence (same PANTHER subfamily SF9, one-to-one ortholog); human cardiac-MLCK acts on MLC2v. Supporting Evidence: PMID:16908724 MLCK increased RLC phosphorylation, increased the Ca(2+) sensitivity of isometric force PMID:10409661 Ca(2+) sensitivity of force development was dependent upon the phosphorylation status of the regulatory light chain
GO:0098735 positive regulation of the force of heart contraction	ISS GO_REF:0000024	ACCEPT	Summary: ISS transfer from mouse Myl2 (P51667). Reason: MLCK phosphorylation of the ventricular RLC increases calcium sensitivity, Ca2+-activated force and stretch-activation kinetics in mouse myocardium, and mice with nonphosphorylatable MLC2v have reduced calcium sensitivity and cardiac dysfunction. MYL2 is the protein whose phosphorylation carries this regulatory effect. Mouse evidence (same PANTHER subfamily SF9, one-to-one ortholog); human cardiac-MLCK acts on MLC2v. Supporting Evidence: PMID:16908724 MLCK increased RLC phosphorylation, increased the Ca(2+) sensitivity of isometric force PMID:17885681 cardiac-specific myosin light chain kinase (cardiac-MLCK), which acts on MLC2v

Gene Description

Existing Annotations Review

Core Functions

Regulatory light chain of sarcomeric (beta-cardiac/slow) myosin II: binds the heavy-chain neck and acts as a structural constituent of the thick filament in the A band.

Binds the class II myosin heavy chain through its conserved central domain, forming the light-chain-heavy-chain lever-arm assembly.

Phospho-regulated tuning of cardiac force: phosphorylation of MYL2 (by cardiac MLCK) raises the calcium sensitivity and magnitude of force and speeds stretch activation (mouse evidence, orthologous).

Ca2+/Mg2+ binding through the first EF hand, measured directly for the human protein and modulated by Ser15 phosphorylation.

References

Suggested Questions for Experts

Suggested Experiments

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Notes

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