CSRP3

Summary: Conserved modulation of cardiac force is a physiological context of MLP.

Reason: The literal mouse P50462 donor has the exact IGI annotation from PMID:10555147. Its complete abstract reports phospholamban-dependent rescue of calcium cycling and contractility in a genetic cardiomyopathy model; the original full text remains unavailable. The independently read PMID:12507422 identifies the MLP/PLN double knockout and discusses secondary relief of mechanical stress. Retain the curated physiological association, without assigning MLP a motor activity or direct control of the calcium pump. The compact core is its performed structural contribution.

Summary: MLP participates in the cardiac response to mechanical load.

Reason: PMID:12507422 measures selective loss of stretch-induced BNP/ANF expression in neonatal mouse MLP-null cardiomyocytes, while hormonal responses remain. Those are markers of a hypertrophic program, not measurements of cardiomyocyte enlargement. Retain the contextual growth response with that endpoint limitation; a general cell-size-control activity is not established.

Summary: The reported interaction with LDHD is retained.

Reason: The complete PMID:12127981 abstract explicitly reports interaction of mammalian D-lactate dehydrogenase proteins with CRP3/MLP, and the original human source identifies Q86WU2. The full experimental text was not recovered. This positive interaction does not transfer dehydrogenase activity or establish a dedicated metabolic-adaptor role. Retain supported generic binding under the project instruction.

Summary: The verified ACTN2 interaction supports muscle alpha-actinin binding.

Reason: The original PMID:15205937 Methods use complete human MLP and alpha-actinin-2 cDNAs, with purified recombinant binding and competition assays. The literal source partner P35609 is ACTN2. GO:0051371 describes binding to muscle alpha-actinin isoforms and is more informative than generic protein binding. The recombinant ternary-complex evidence is not a native stoichiometry measurement.

Proposed replacements: muscle alpha-actinin binding

Summary: N-RAP is a verified cytoskeletal binding partner.

Reason: PMID:15205937 directly tests human N-RAP fragments 1–121 and 1–183 with recombinant human MLP and alpha-actinin. Binding and noncompetition support a cytoskeletal-protein interaction, the role described by GO:0008092. This does not establish an adaptor mechanism or a named native complex. The inferred N-RAP binding region is not automatically a recognized domain-specific molecular function.

Proposed replacements: cytoskeletal protein binding

Summary: The positive TCAP interaction is specifically telethonin binding.

Reason: The source partner O15273 is telethonin. Actual indexed JACC Methods from PMID:15582318 identify human MLP residues 1–194 and TCAP constructs, yeast two-hybrid tests and purified recombinant GST pull-down competition; target-bearing Results and Table 3 confirm the interaction. Refine to the existing specific telethonin-binding term. Disease mechanisms proposed from these in-vitro assays are separate from the demonstrated binding.

Proposed replacements: telethonin binding

Summary: The TCAP association supports telethonin binding with product-specific limits.

Reason: PMID:24860983 recovers telethonin in GST-MLP-b tissue pull-downs, using full-length MLP-a as a positive control. These are tissue-extract associations rather than purified binary contacts. The literal O15273 identity supports GO:0031433. MINT maps the CSRP3 backbone to the 194-residue sequence even where the assay comments specify historical MLP-b; the backbone identifier is not proof of the tested isoform. Results call the extract cardiac, while Methods call it skeletal; neither wording is silently replaced.

Proposed replacements: telethonin binding

Summary: The ACTN2 association supports muscle alpha-actinin binding.

Reason: The original annotation identifies P35609/ACTN2. PMID:24860983 reports alpha-actinin recovery with historical MLP-b and a full-length MLP-a positive control from tissue extract. The specific partner class supports GO:0051371, without claiming purified direct contact or identical activity of both current products. Preserve the source assay and the cardiac-versus-skeletal extract wording discrepancy.

Proposed replacements: muscle alpha-actinin binding

Summary: Full-length MLP binds the cytoskeletal regulator cofilin-2.

Reason: PMID:24860983 directly compares recombinant proteins: full-length MLP-a binds CFL2, whereas historical MLP-b does not. CFL2 is an actin-associated regulatory component of the cytoskeleton, not a structural actin subunit; GO:0008092 classifies the bound cytoskeletal protein without asserting incorporation into the filament backbone or a cofilin-specific activity. The same source shows that MLP-b does not displace the MLP-a/CFL2 interaction. PMID:19752190 and PMID:24934443 report differing effects on actin depolymerization, so binding is not converted into a universal activation mechanism.

Proposed replacements: cytoskeletal protein binding

Summary: The HTT-screen interaction is retained at its measured scope.

Reason: Three complete IntAct records from PMID:32814053 identify the CSRP3–HTT pair in systematic yeast two-hybrid formats. Participant sequence checks support the recorded backbones; HTT assay features identify an N-terminal 1–546 construct and a variable polyglutamine tract. These positive records do not establish a native full-length complex, neuronal physiological role or a specific molecular activity for CSRP3. Generic binding is retained under the standing project instruction.

Summary: The inherited nuclear location is consistent with MLP biology.

Reason: PTHR24215 places the exact 194-residue human sequence at PTN002516901 below the asserted PTN001198226 ancestor, where the nucleus IBD is present. This is a phylogenetic placement, not a donor-count argument. The complete PMID:9234731 abstract explicitly describes nuclear MLP and interaction with myogenic transcription factors; HPA also reports nucleoplasm in THP-1 cells. Nuclear localization need not be exclusive or define the structural core.

Summary: The curated nuclear location is supported.

Reason: The actual source SL-0191 is the UniProt nucleus mapping. It agrees with the nuclear MLP and myogenic-transcription-factor context explicitly described in PMID:9234731. This does not imply that every product or every muscle state is predominantly nuclear.

Summary: The broad cytoplasmic location is valid.

Reason: The exact human target is descended from PTN001198224 and the current cytoplasm IBD is present at that node. Its broad source scope is compatible with cytosolic and sarcomeric MLP pools, including the human muscle observations in PMID:24860983. The human source in the IBD is legitimate descendant evidence rather than circularity.

Summary: The UniProt cytoplasmic mapping is appropriate.

Reason: SL-0086 maps the source annotation to cytoplasm. The directly described cytoplasmic and Z-disc pools of MLP are compatible with this broad location; the term is not an assertion that MLP is exclusively soluble.

Summary: A cytosolic pool has HPA and independent construct-localization support.

Reason: The actual HPA XML reports cytosol in U2OS and THP-1, with additional nucleoplasm in THP-1. Antibody subassay validation is supported but overall localization reliability is uncertain, so this is not treated as conclusive native muscle-cell evidence. Independently, PMID:24934443 reports diffuse cytosolic and nuclear signal for full-length human MLP-Venus expressed in mouse C2C12 cells, alongside stress-fiber localization. This supports a cytosolic pool with explicit overexpression, host-species and product limits; it does not establish identical localization for the short product.

Summary: Cytoskeletal association is independently demonstrated.

Reason: The literal source is UniProt SL-0090. Direct actin binding, bundling and protection by recombinant human MLP, together with cellular cytoskeletal association, support this general location. More precise Z-disc annotations coexist; they do not exhaust all experimentally observed cytoskeletal contexts.

Summary: Calcium homeostasis is a supported cardiac physiological context.

Reason: The exact mouse P50462 source carries the IGI assertion from PMID:10555147. Its accessible abstract describes calcium-cycling rescue by phospholamban removal; PMID:12507422 explicitly discusses the MLP/PLN model and distinguishes secondary stress relief from a primary calcium-signaling mechanism. Retain the curated context without asserting that MLP transports calcium or directly regulates SERCA. Full access to the 1999 original remains unavailable.

Summary: MLP has a documented role in myogenic differentiation.

Reason: The complete PMID:7954791 abstract reports impaired differentiation after MLP inhibition and enhanced differentiation after overexpression in C2 myoblasts. The full original and exact construct species were not recovered, so the cited tissue-development interpretation is retained with curator deference rather than embellished. Later human MLP expression in mouse C2C12 cells supports product-dependent myotube effects. This is a developmental context beyond the compact structural core.

Summary: The inherited structural muscle activity is supported by performed molecular work.

Reason: The exact target is below PTN001198226 and its current GO:0008307 IBD is present. Direct human MLP–actin binding and cross-linking provide independent structural activity, complementing mouse loss-of-function and human molecular evidence. The current short product is not assumed to share the full-length activity.

Summary: The mouse-to-human structural-function inference is supported.

Reason: The literal UniProt P50462/Ensembl donor route has current experimental mouse support from PMID:12507422. Independent direct recombinant human MLP actin-binding and bundling assays establish structural work rather than merely a requirement for a phenotype. The transfer is therefore compatible with the human target.

Summary: MLP supplies a structural contribution to muscle integrity.

Reason: PMID:12507422 links MLP loss to altered Z-disc organization, telethonin retention and mechanical behavior, with human binding/disease evidence and rodent experiments distinguished. PMID:24934443 independently demonstrates human MLP binding and cross-linking actin filaments. The activity is structural, not intrinsic force generation.

Summary: The sarcomere mapping is valid at its source resolution.

Reason: The UniProt SL-0313 sarcomere mapping is consistent with the directly described Z-disc localization, already represented by separate source annotations. Accept the broader electronic location without asserting that all isoforms or all cellular pools are sarcomeric.

Summary: The inherited Z-disc location is supported.

Reason: The target is below PTN001198226 and the current Z-disc IBD is present there. Rodent localization and human skeletal-muscle isoform-directed immunostaining independently support this location. The multiple descendant sources are not used as a confidence vote.

Summary: The original Z-disc localization is retained.

Reason: PMID:12507422 reports MLP/telethonin coimmunostaining in neonatal rat cardiomyocytes and distinct human mutation/localization observations; these are not an all-human unperturbed localization series. The independent human quadriceps staining in PMID:24860983 corroborates the gene-level Z-disc location.

Summary: The combined electronic Z-disc mapping is supported.

Reason: The literal combined route names mouse P50462, its Ensembl protein and SL-0314. Current mouse localization annotations and the UniProt subcellular mapping are compatible with the human Z-disc evidence in PMID:24860983. Preserve the exact combined source rather than replacing it with a different method.

Summary: Telethonin binding is directly supported.

Reason: PMID:12507422 reports yeast two-hybrid interaction, deletion mapping and a GST-MLP pull-down with reticulocyte-translated telethonin. Colocalization and telethonin redistribution provide distinct cellular observations. This is a specific binding function; the assay does not establish native complex stoichiometry.

Summary: Conserved telethonin binding is a sound orthology transfer.

Reason: Current mouse P50462 has the exact experimental telethonin-binding annotation from PMID:12507422. The original UniProt/Ensembl route is retained, and independent human MLP/TCAP recombinant binding in PMID:15582318 corroborates target compatibility.

Summary: The original TCAP interaction supports the specific binding term.

Reason: PMID:15582318 uses human MLP residues 1–194 and TCAP constructs in yeast two-hybrid and purified recombinant competition assays. Its target-bearing Results and Table 3 distinguish altered mutant binding from baseline positive interaction. Retain telethonin binding without importing the speculative cardiomyopathy mechanism.

Summary: MLP contributes structurally to muscle stretch detection.

Reason: Current mouse P50462 carries the matching experimental assertion from PMID:12507422. In that source, MLP-null papillary muscles and neonatal cardiomyocytes have selective passive-stretch defects while several other responses remain. The human protein can participate by organizing the Z-disc sensor machinery; this does not establish MLP as an autonomous force sensor.

Summary: The source supports participation in the muscle stretch-detection machinery.

Reason: PMID:12507422 measures altered passive stress–strain behavior and selective loss of stretch-induced BNP/ANF responses. MLP–telethonin interaction and structural organization support a performed structural role. The paper proposes titin as the intrinsic elastic sensor, while downstream coupling remains unresolved; MLP is not assigned an autonomous receptor activity.

Summary: Full-length MLP self-association is independently supported.

Reason: The original PMID:24860983 experiment specifically tests nonidentical MLP-a and historical MLP-b, so its P50461 backbone mapping alone cannot establish identical-protein binding. Independently, PMID:24934443 shows full-length human MLP self-association by BiFC in mouse C2C12/HL-1 cells and maps its importance to actin bundling. Retain the gene-level function with this explicit source distinction, without equating current 58-residue and historical 59-residue products.

Summary: The inherited actinin-binding biology can be expressed as alpha-actinin binding.

Reason: The target descends from PTN001198226, which has the actual actinin-binding IBD. That broader assertion is supported; it is not a propagation failure. Original MLP literature explicitly identifies alpha-actinin, and the current GO child GO:0051393 captures this family-level specificity. Independently identified ACTN2-specific experiments are reviewed separately. The cached PMID:15205937 partner-naming clause corroborates the alpha-actinin class; it does not replace the original source-specific donor or ancestral evidence.

Proposed replacements: alpha-actinin binding

Summary: The mouse actinin-binding transfer supports alpha-actinin specificity.

Reason: The current mouse P50462 exact binding annotation is experimentally grounded in PMID:12507422, whose original text identifies alpha-actinin. Refine the valid broader assertion to GO:0051393, retaining its UniProt/Ensembl provenance. The unidentified clone is not labeled ACTN2 solely because it originated from a heart library. The cached PMID:15205937 partner-naming clause corroborates the alpha-actinin class; it does not replace the original source-specific donor or ancestral evidence.

Proposed replacements: alpha-actinin binding

Summary: The original alpha-actinin identity supports a narrower binding term.

Reason: PMID:12507422 explicitly identifies alpha-actinin in its yeast two-hybrid and deletion-mapping assays. GO:0051393 is a verified child of actinin binding. The original mouse ISS tuple is retained; the assay clone accession is insufficiently specified to choose the narrower muscle-isoform child from this source alone. The cached PMID:15205937 partner-naming clause corroborates the alpha-actinin class; it does not replace the original source-specific donor or ancestral evidence.

Proposed replacements: alpha-actinin binding

Summary: The inherited sarcomere-organization function is supported.

Reason: The exact human target is descended from PTN001198226 and the sarcomere-organization IBD is present. Current descendant experimental records, including both zebrafish accessions associated with the literal ZFIN identifier, are preserved without arbitrarily choosing one. Direct human actin cross-linking and the original Z-disc findings support structural participation.

Summary: The conserved structural organization role supports the electronic transfer.

Reason: Current mouse P50462 has the exact experimental sarcomere-organization annotation from PMID:12507422. Its structural interpretation is compatible with direct human MLP actin-binding and bundling evidence, not simply a transfer from a generic disease phenotype.

Summary: MLP contributes to the organization and integrity of the sarcomere.

Reason: The original PMID:12507422 reports altered Z-disc alignment and telethonin localization in MLP-null muscle, with phospholamban removal rescuing secondary structural defects. Direct MLP binding and later actin cross-linking establish a structural contribution. This is not described as a directly measured assembly rate.

Summary: Positive myogenic transcriptional regulation is retained.

Reason: The original P10085 source is mouse Myod1. The complete PMID:9234731 abstract reports physical MLP–MyoD interaction and increased DNA binding of the MyoD–E47 complex, while explicitly stating that MLP lacks its own activation domain. Full original recovery failed, so detailed reporter and construct claims are not invented. The positive nuclear regulatory context is retained apart from the compact structural core.

Summary: The MRF4-associated positive transcriptional context is retained.

Reason: The source P19335 identifies mouse Myf6/MRF4, one of the muscle bHLH factors explicitly named in the complete PMID:9234731 abstract. The original full text remains unavailable; the MyoD-specific DNA-binding result is not silently treated as an MRF4-specific assay. Retain the curator-supported contextual annotation without assigning a universal autonomous transactivation activity.

Summary: Cardiac muscle development is retained as an ortholog-supported context.

Reason: The exact mouse P50462 annotation is an IGI assertion from PMID:10555147. The accessible abstract addresses calcium-cycling rescue of a genetic cardiomyopathy model, and the complete original was not recovered; it does not by itself resolve developmental timing. Independent structural evidence makes the broad cardiac-muscle context compatible, but it is not a separate embryonic specification function or a direct human developmental assay.

Summary: The cardiac myofibril contribution is compatible with the orthology source.

Reason: Current mouse P50462 carries the matching experimental annotation from PMID:12507422. Structural MLP interactions and Z-disc organization support participation in formation and maturation of cardiac myofibrils. The original source and species are retained; a direct human assembly-rate measurement is not claimed.

Summary: The mouse-source cardiac myofibril role is retained.

Reason: PMID:12507422 provides structural organization, interaction and physiological evidence in mouse and rodent preparations, with separate human mutation/binding observations. This supports the conserved structural myofibril contribution without equating the source to a direct human myofibril-assembly experiment.

Summary: The inherited contraction role is a structural contribution.

Reason: The exact human target descends from PTN002794838 and the current cardiac-muscle-contraction IBD is present there. Mouse and human experimental grounding is legitimate descendant evidence. MLP supports force-transmitting structures; it need not be an actin motor to participate in contraction.

Summary: The electronic contraction annotation is supported at structural scope.

Reason: The current mouse P50462 source has the exact experimental annotation from PMID:12507422. This is compatible with human MLP structural interactions and actin cross-linking. Retain the orthology route without claiming that MLP itself generates contractile force.

Summary: MLP contributes structurally to cardiac contractile function.

Reason: PMID:12507422 links MLP loss to mechanical abnormalities and progressive contractile dysfunction, with a preserved recovery response in the tested passive-stretch assay. Specific structural interactions and independent actin cross-linking support participation. The result is not evidence for an intrinsic motor or a universal defect in every contraction parameter.

Summary: The inherited muscle-development context is retained.

Reason: PTN001198226 lies on the verified human path and carries the actual muscle-tissue-development IBD. The current fly donor provides expression evidence, while other source snapshots differ; this does not negate the ancestral placement or make a short source list weak. The myogenic perturbation evidence in PMID:7954791 and product-dependent differentiation in PMID:24860983 support a contextual developmental role.

Summary: Telethonin retention supports maintenance at the Z disc rather than directed delivery.

Reason: The exact mouse P50462 experimental assertion and paired Ensembl transfer remain the original provenance. The full PMID:12507422 original reports telethonin redistribution and increased soluble recovery in MLP-null mouse myocardium, with preservation in the MLP/PLN double knockout, together with direct MLP–telethonin interaction evidence. Human W4R patient observations are a separate corroborating context. These results support maintaining an already localized pool even though the molecular stabilization mechanism remains unresolved. GO:0072594 asserts directed movement, which is not established here. GO:0032507 maintenance of protein location in cell was considered; its child GO:0072595 is more precise for retention at the Z disc, a sarcomeric organelle component. The term correction is shared by source and target and does not declare the mouse evidence invalid.

Proposed replacements: maintenance of protein localization in organelle

Summary: Telethonin retention supports maintenance at the Z disc rather than directed delivery.

Reason: The full PMID:12507422 original reports telethonin redistribution and increased soluble recovery in MLP-null mouse myocardium, with preservation in the MLP/PLN double knockout, together with direct MLP–telethonin interaction evidence. Human W4R patient observations are a separate corroborating context. These results support maintaining an already localized pool even though the molecular stabilization mechanism remains unresolved. GO:0072594 asserts directed movement, which is not established here. GO:0032507 maintenance of protein location in cell was considered; its child GO:0072595 is more precise for retention at the Z disc, a sarcomeric organelle component. The term correction is shared by source and target and does not declare the mouse evidence invalid.

Proposed replacements: maintenance of protein localization in organelle