{"gene":"CSRP3","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":1997,"finding":"MLP (CSRP3) knockout mice develop dilated cardiomyopathy with disruption of cardiomyocyte cytoarchitecture, establishing that MLP promotes proper cardiomyocyte cytoarchitecture organization at actin-based structures in terminally differentiated striated muscle cells.","method":"Gene knockout in mice (MLP-deficient), ultrastructural analysis, in vivo cardiac phenotyping","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, foundational paper with >680 citations, replicated by multiple subsequent studies","pmids":["9039266"],"is_preprint":false},{"year":2000,"finding":"MLP (CSRP3) interacts with betaI-spectrin via its second LIM motif (binding to repeat 7 of beta-spectrin), and the two proteins co-localize at the sarcolemma overlying Z- and M-lines of myofibrils in cardiac and skeletal muscle, suggesting MLP functions as a costamere protein linking the beta-spectrin network to alpha-actinin crosslinked actin filaments.","method":"Yeast two-hybrid screen, in vitro and in vivo protein interaction assays, confocal microscopy co-localization","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assays plus localization, multiple orthogonal methods in single study","pmids":["10751147"],"is_preprint":false},{"year":2000,"finding":"MLP protein is present in the contractile protein fraction of cardiomyocytes, and its binding to myofibrils requires functional zinc finger (LIM) domains; MLP protein (but not mRNA) is decreased ~50% in failing human hearts, suggesting post-translational regulation.","method":"Western blot fractionation, domain mutagenesis, Northern blot, immunohistochemistry","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 — fractionation with domain mutagenesis, single lab","pmids":["10851202"],"is_preprint":false},{"year":2003,"finding":"MLP and ALP (a related PDZ-LIM protein) distribute to distinct subcellular compartments during myofibrillogenesis in cardiomyocytes: ALP co-distributes with alpha-actinin to Z-lines from the earliest stages, while MLP localizes to premyofibrils and nascent myofibrils before costamere establishment, suggesting MLP functions during differentiation prior to costamere formation.","method":"Immunofluorescence microscopy during myofibrillogenesis in cultured embryonic chick cardiomyocytes, GFP transfection, in vitro binding assay","journal":"Cell motility and the cytoskeleton","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiments with functional context, single lab","pmids":["12589684"],"is_preprint":false},{"year":2008,"finding":"CSRP3 missense mutations cause hypertrophic cardiomyopathy (HCM); MLP is mainly a cytosolic component of cardiomyocytes (not tightly anchored to sarcomeric structures); at least one HCM-associated mutant form of MLP is destabilized in patient hearts.","method":"Linkage analysis, monoclonal antibody-based immunolocalization, in vitro and in vivo functional analysis of mutant MLP stability","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple families with segregating mutations, antibody localization, and functional destabilization data; strong evidence","pmids":["18505755"],"is_preprint":false},{"year":2009,"finding":"The W4R (Trp4Arg) MLP variant causes reduced MLP mRNA and protein expression, weaker in vitro interaction of telethonin with W4R-MLP compared to wild-type MLP, and increased nuclear localization of W4R-MLP; knock-in mice develop age- and gene dosage-dependent hypertrophic cardiomyopathy.","method":"Knock-in mouse generation, in vitro binding assay (telethonin-MLP interaction), immunohistochemistry, Western blot","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — knock-in animal model with multiple orthogonal methods including binding assay and localization","pmids":["20044516"],"is_preprint":false},{"year":2009,"finding":"CRP3/MLP expression in vascular smooth muscle cells is induced by mechanical stretch (not shear stress) during vein arterialization, identifying stretch as the primary biomechanical stimulus for CSRP3 induction in this context.","method":"Ex vivo flow-through system mimicking arterial conditions, in vivo rat vein arterialization model, quantitative RT-PCR, immunostaining","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and ex vivo models with controlled mechanical stimuli, single lab","pmids":["19351738"],"is_preprint":false},{"year":2015,"finding":"MLP (CSRP3) contributes to correct autophagosome formation and flux in muscle cells by directly interacting with LC3, as demonstrated by co-immunoprecipitation and proximity ligation assay; MLP silencing results in decreased LC3-II, impaired degradation of long-lived proteins, and increased apoptotic susceptibility.","method":"Co-immunoprecipitation, proximity ligation assay (PLA), siRNA knockdown, Western blot, ultrastructural analysis","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP plus PLA for interaction, KD phenotype; single lab but two orthogonal interaction methods","pmids":["27551448"],"is_preprint":false},{"year":2019,"finding":"Syndecan-4 directly binds MLP (CSRP3) with increased binding in heart failure; syndecan-4 mediates nuclear translocation of MLP in cardiomyocytes, as loss of syndecan-4 reduces nuclear MLP and overexpression increases it; a cell-permeable syndecan-4–MLP disruptor peptide reduces nuclear MLP levels.","method":"Affinity purification-MS interactome mapping, co-immunoprecipitation validation in HEK293 cells, nuclear fractionation of syndecan-4 knockout and overexpression models, disruptor peptide experiment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, nuclear fractionation with genetic and peptide perturbation, MS-based interactome; multiple orthogonal methods","pmids":["30967474"],"is_preprint":false},{"year":2019,"finding":"MLP-deficient hESC-derived cardiomyocytes develop HCM-like phenotypes (enlarged cell size, disorganized sarcomere, mitochondrial damage) that progress to heart failure features; restoration of Ca2+ homeostasis with verapamil prevents these phenotypes, indicating that elevated intracellular Ca2+ is a central mechanistic consequence of MLP deficiency.","method":"CRISPR/Cas9 knockout of CSRP3 in hESCs, differentiation to cardiomyocytes, calcium imaging, pharmacological rescue with verapamil","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — human genetic KO model with pharmacological rescue defining calcium handling as central mechanism","pmids":["31406109"],"is_preprint":false},{"year":2020,"finding":"S-nitrosylation of MLP at cysteine 79 (SNO-MLP) is elevated in hypertrophic myocardium and drives myocardial hypertrophy by promoting MLP binding to TLR3, which in turn increases TLR3–RIP3 complex formation and NLRP3 inflammasome activation; mutation of Cys79 or overexpression of GSNO reductase reduces hypertrophic growth.","method":"Biotin-switch assay for SNO detection, LC-MS/MS for SNO site identification, site-directed mutagenesis (C79 mutation), co-immunoprecipitation, siRNA knockdown of TLR3, TLR3 knockout mouse model, transverse aortic constriction model","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1-2 — SNO site identified by MS and confirmed by mutagenesis, downstream pathway confirmed by KO mouse and co-IP; multiple orthogonal methods","pmids":["31902237"],"is_preprint":false},{"year":2019,"finding":"Knockdown of CSRP3 in chicken satellite cells inhibits myotube differentiation (but not proliferation) by upregulating TGF-β/Smad3 signaling, including increased Smad3 phosphorylation, identifying CSRP3 as a positive regulator of satellite cell differentiation acting upstream of TGF-β/Smad3.","method":"siRNA knockdown, overexpression, Western blot for Smad3 phosphorylation, qRT-PCR, differentiation assays","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 — KD/OE with pathway placement via phospho-Smad3, single lab, chicken model","pmids":["30930226"],"is_preprint":false},{"year":2020,"finding":"CSRP3/MLP interacts with LC3 protein to promote autophagosome formation; CSRP3 silencing impairs autophagy (reduced ATG5, ATG7, LC3-II, Beclin-1) and increases apoptosis via caspase-3/9 cleavage in chicken myoblasts; autophagy activation rescues the apoptotic phenotype.","method":"siRNA knockdown, co-immunoprecipitation, Western blot, pharmacological autophagy activation rescue","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP for interaction, KD phenotype with rescue; single lab, avian model","pmids":["31979369"],"is_preprint":false},{"year":2022,"finding":"Vitamin C promotes nuclear translocation of CSRP3, and nuclear CSRP3 interacts directly with myogenic transcription factors MyoD and MyoG to promote muscle differentiation and repair.","method":"Transcriptomics, proteomics, co-immunoprecipitation, nuclear translocation assays in C2C12 cells and mouse muscle injury model","journal":"Journal of agricultural and food chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP demonstrating interaction with MyoD/MyoG, nuclear localization shown, single lab","pmids":["35652451"],"is_preprint":false}],"current_model":"CSRP3/MLP is a dual-compartment LIM-only protein in striated muscle that maintains cardiomyocyte cytoarchitecture by linking actin filaments at costameres (via betaI-spectrin and alpha-actinin) and at the sarcomeric Z-line; it undergoes nuclear translocation (facilitated by syndecan-4) where it interacts with myogenic transcription factors, regulates autophagy through direct LC3 binding, and when S-nitrosylated at Cys79 recruits TLR3 to activate RIP3-NLRP3 inflammasome signaling, with loss-of-function or disease-causing missense mutations disrupting these interactions and leading to dilated or hypertrophic cardiomyopathy partly through dysregulation of calcium handling."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing that CSRP3 is required for cardiomyocyte cytoarchitecture answered the fundamental question of whether this LIM-domain protein has a structural role in terminally differentiated muscle, rather than being purely transcriptional.","evidence":"MLP knockout mice developing dilated cardiomyopathy with disrupted actin-based structures, ultrastructural and cardiac phenotyping","pmids":["9039266"],"confidence":"High","gaps":["Specific molecular partners at the cytoskeleton not yet identified","Whether the phenotype reflects a structural versus signaling defect was unresolved"]},{"year":2000,"claim":"Identifying βI-spectrin as a direct binding partner of the second LIM domain and demonstrating co-localization at costameres established CSRP3 as a physical linker between the spectrin membrane skeleton and the sarcomeric actin cytoskeleton.","evidence":"Yeast two-hybrid, in vitro binding assays, confocal co-localization at sarcolemma overlying Z- and M-lines","pmids":["10751147"],"confidence":"High","gaps":["Whether CSRP3 bridges spectrin and α-actinin simultaneously was not tested","Role at premyofibril versus mature costamere stages was unclear"]},{"year":2003,"claim":"Tracking CSRP3 localization during myofibrillogenesis revealed it acts at premyofibril and nascent myofibril stages before costamere formation, distinguishing its temporal role from that of the related PDZ-LIM protein ALP.","evidence":"Immunofluorescence during cardiomyocyte differentiation in embryonic chick cultures","pmids":["12589684"],"confidence":"Medium","gaps":["Whether premyofibril localization is functionally required was not tested by perturbation","Mammalian validation not performed"]},{"year":2008,"claim":"Demonstrating that CSRP3 missense mutations segregate with hypertrophic cardiomyopathy and that mutant protein is destabilized in patient hearts established CSRP3 as a bona fide HCM disease gene and showed that its predominant localization is cytosolic rather than tightly sarcomere-anchored.","evidence":"Linkage analysis in multiple families, monoclonal antibody immunolocalization, mutant protein stability assays","pmids":["18505755"],"confidence":"High","gaps":["Mechanism by which destabilization leads to hypertrophy not defined","Whether all HCM mutations act through destabilization versus altered interactions was unknown"]},{"year":2009,"claim":"The W4R knock-in mouse showed that a specific HCM-linked mutation weakens telethonin binding and increases nuclear MLP accumulation, establishing that disease mutations can alter both protein–protein interactions and subcellular distribution in a dosage- and age-dependent manner.","evidence":"Knock-in mice, in vitro telethonin–MLP binding assay, immunohistochemistry, Western blot","pmids":["20044516"],"confidence":"High","gaps":["Whether increased nuclear MLP is pathogenic or compensatory was unclear","The nuclear function of MLP remained undefined"]},{"year":2015,"claim":"Discovery that CSRP3 directly binds LC3 and is required for proper autophagosome formation revealed a previously unsuspected role in muscle autophagy, linking its loss to impaired protein turnover and increased apoptotic vulnerability.","evidence":"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown with autophagic flux measurements","pmids":["27551448"],"confidence":"Medium","gaps":["The LC3-binding domain on CSRP3 was not mapped","Whether autophagy impairment contributes to the cardiomyopathy phenotype in vivo was untested"]},{"year":2019,"claim":"Identification of syndecan-4 as a direct CSRP3 interactor that mediates its nuclear translocation resolved the long-standing question of how a predominantly cytoskeletal protein accesses the nucleus, and showed this interaction is enhanced in heart failure.","evidence":"Affinity purification-MS, reciprocal co-IP, nuclear fractionation in syndecan-4 KO/overexpression models, disruptor peptide","pmids":["30967474"],"confidence":"High","gaps":["Nuclear targets of translocated MLP were not identified in this study","Whether syndecan-4–MLP disruption is therapeutic in heart failure models was not shown"]},{"year":2019,"claim":"CRISPR knockout of CSRP3 in human cardiomyocytes showed that elevated intracellular calcium is a central consequence of MLP loss, and pharmacological calcium normalization prevents HCM-like progression to heart failure, establishing calcium dysregulation as a unifying downstream mechanism.","evidence":"CSRP3 CRISPR KO in hESC-derived cardiomyocytes, calcium imaging, verapamil rescue","pmids":["31406109"],"confidence":"High","gaps":["The molecular basis of calcium elevation (channel, SERCA, leak) was not defined","Whether calcium normalization rescues in vivo models was untested"]},{"year":2020,"claim":"Identification of S-nitrosylation at Cys79 as a post-translational modification that converts CSRP3 into a pro-hypertrophic signaling molecule—by enabling TLR3 binding and RIP3–NLRP3 inflammasome activation—revealed a gain-of-function inflammatory mechanism distinct from loss-of-function structural roles.","evidence":"Biotin-switch assay, LC-MS/MS SNO-site mapping, C79 mutagenesis, TLR3 co-IP and KO mouse, transverse aortic constriction model","pmids":["31902237"],"confidence":"High","gaps":["Whether SNO-MLP-TLR3 axis operates in human heart failure tissue was not shown","The nitrosylase/denitrosylase balance controlling Cys79 modification in vivo is unclear"]},{"year":2022,"claim":"Demonstrating that nuclear CSRP3 directly interacts with MyoD and MyoG identified transcription-factor partners and provided a molecular function for nuclear MLP in promoting myogenic differentiation and repair.","evidence":"Co-immunoprecipitation in C2C12 cells, nuclear translocation assays, mouse muscle injury model","pmids":["35652451"],"confidence":"Medium","gaps":["Whether CSRP3 acts as a co-activator or chromatin remodeler at myogenic promoters is unknown","Genome-wide binding sites of CSRP3 have not been determined"]},{"year":null,"claim":"How the cytoskeletal scaffolding, autophagy-promoting, and nuclear transcriptional co-regulatory functions of CSRP3 are coordinated in response to mechanical load, and which function is primarily disrupted in each cardiomyopathy-causing mutation, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of CSRP3 LIM domains bound to any partner exists","The molecular basis of calcium dysregulation upon CSRP3 loss is not defined","Whether autophagy impairment contributes to in vivo cardiomyopathy phenotypes is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,8,10]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,8,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,4,5,9]}],"complexes":[],"partners":["SPTBN1","ACTN2","SDC4","TCAP","MAP1LC3B","TLR3","MYOD1","MYOG"],"other_free_text":[]},"mechanistic_narrative":"CSRP3 (MLP) is a LIM-domain protein essential for striated muscle cytoarchitecture, mechanotransduction, and cardiomyocyte survival. At the cytoskeleton, CSRP3 links actin-based structures to the sarcolemma by binding βI-spectrin at costameres and α-actinin at Z-lines, and its loss causes dilated cardiomyopathy with disrupted myofibrillar organization and dysregulated calcium homeostasis that can be rescued by calcium channel blockade [PMID:9039266, PMID:10751147, PMID:31406109]. CSRP3 undergoes syndecan-4-dependent nuclear translocation where it interacts with myogenic transcription factors MyoD and MyoG to promote muscle differentiation, and in the cytoplasm it directly binds LC3 to support autophagosome formation, with its silencing impairing autophagic flux and increasing apoptosis [PMID:30967474, PMID:35652451, PMID:27551448]. Missense mutations in CSRP3 cause hypertrophic cardiomyopathy through protein destabilization and disrupted interactions, while S-nitrosylation at Cys79 in hypertrophic myocardium drives pathological signaling by recruiting TLR3 to activate the RIP3–NLRP3 inflammasome pathway [PMID:18505755, PMID:20044516, PMID:31902237]."},"prefetch_data":{"uniprot":{"accession":"P50461","full_name":"Cysteine and glycine-rich protein 3","aliases":["Cardiac LIM protein","Cysteine-rich protein 3","CRP3","LIM domain protein, cardiac","Muscle LIM protein"],"length_aa":194,"mass_kda":21.0,"function":"Positive regulator of myogenesis. Acts as a cofactor for myogenic bHLH transcription factors such as MYOD1, and probably MYOG and MYF6. Enhances the DNA-binding activity of the MYOD1:TCF3 isoform E47 complex and may promote formation of a functional MYOD1:TCF3 isoform E47:MEF2A complex involved in myogenesis (By similarity). Plays a crucial and specific role in the organization of cytosolic structures in cardiomyocytes. Could play a role in mechanical stretch sensing. May be a scaffold protein that promotes the assembly of interacting proteins at Z-line structures. It is essential for calcineurin anchorage to the Z line. Required for stress-induced calcineurin-NFAT activation (By similarity). The role in regulation of cytoskeleton dynamics by association with CFL2 is reported conflictingly: Shown to enhance CFL2-mediated F-actin depolymerization dependent on the CSRP3:CFL2 molecular ratio, and also shown to reduce the ability of CLF1 and CFL2 to enhance actin depolymerization (PubMed:19752190, PubMed:24934443). Proposed to contribute to the maintenance of muscle cell integrity through an actin-based mechanism. Can directly bind to actin filaments, cross-link actin filaments into bundles without polarity selectivity and protect them from dilution- and cofilin-mediated depolymerization; the function seems to involve its self-association (PubMed:24934443). In vitro can inhibit PKC/PRKCA activity (PubMed:27353086). Proposed to be involved in cardiac stress signaling by down-regulating excessive PKC/PRKCA signaling (By similarity) May play a role in early sarcomere organization. Overexpression in myotubes negatively regulates myotube differentiation. By association with isoform 1 and thus changing the CSRP3 isoform 1:CFL2 stoichiometry is proposed to down-regulate CFL2-mediated F-actin depolymerization","subcellular_location":"Cytoplasm, myofibril, sarcomere, Z line","url":"https://www.uniprot.org/uniprotkb/P50461/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CSRP3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CSRP3","total_profiled":1310},"omim":[{"mim_id":"617195","title":"MUSCULOSKELETAL EMBRYONIC NUCLEAR PROTEIN 1; MUSTN1","url":"https://www.omim.org/entry/617195"},{"mim_id":"615396","title":"LEFT VENTRICULAR NONCOMPACTION 10; LVNC10","url":"https://www.omim.org/entry/615396"},{"mim_id":"612754","title":"GLUTAREDOXIN 3; GLRX3","url":"https://www.omim.org/entry/612754"},{"mim_id":"612124","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 12; CMH12","url":"https://www.omim.org/entry/612124"},{"mim_id":"609470","title":"LEFT VENTRICULAR NONCOMPACTION 2; LVNC2","url":"https://www.omim.org/entry/609470"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytosol","reliability":"Uncertain"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"heart muscle","ntpm":2447.5},{"tissue":"skeletal muscle","ntpm":1545.8},{"tissue":"tongue","ntpm":540.3}],"url":"https://www.proteinatlas.org/search/CSRP3"},"hgnc":{"alias_symbol":["CLP","MLP","CMD1M"],"prev_symbol":[]},"alphafold":{"accession":"P50461","domains":[{"cath_id":"2.10.110.10","chopping":"8-85","consensus_level":"medium","plddt":82.154,"start":8,"end":85},{"cath_id":"2.10.110.10","chopping":"131-175","consensus_level":"high","plddt":86.8909,"start":131,"end":175}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P50461","model_url":"https://alphafold.ebi.ac.uk/files/AF-P50461-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P50461-F1-predicted_aligned_error_v6.png","plddt_mean":73.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CSRP3","jax_strain_url":"https://www.jax.org/strain/search?query=CSRP3"},"sequence":{"accession":"P50461","fasta_url":"https://rest.uniprot.org/uniprotkb/P50461.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P50461/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P50461"}},"corpus_meta":[{"pmid":"9039266","id":"PMC_9039266","title":"MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure.","date":"1997","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9039266","citation_count":680,"is_preprint":false},{"pmid":"15554981","id":"PMC_15554981","title":"Clp ATPases are required for stress tolerance, intracellular replication and biofilm formation in Staphylococcus aureus.","date":"2004","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15554981","citation_count":248,"is_preprint":false},{"pmid":"2197275","id":"PMC_2197275","title":"Sequence and structure of Clp P, the proteolytic component of the ATP-dependent Clp protease of Escherichia coli.","date":"1990","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2197275","citation_count":215,"is_preprint":false},{"pmid":"19609260","id":"PMC_19609260","title":"Adapting the machine: adaptor proteins for Hsp100/Clp and AAA+ proteases.","date":"2009","source":"Nature reviews. 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\"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, foundational paper with >680 citations, replicated by multiple subsequent studies\",\n      \"pmids\": [\"9039266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MLP (CSRP3) interacts with betaI-spectrin via its second LIM motif (binding to repeat 7 of beta-spectrin), and the two proteins co-localize at the sarcolemma overlying Z- and M-lines of myofibrils in cardiac and skeletal muscle, suggesting MLP functions as a costamere protein linking the beta-spectrin network to alpha-actinin crosslinked actin filaments.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro and in vivo protein interaction assays, confocal microscopy co-localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays plus localization, multiple orthogonal methods in single study\",\n      \"pmids\": [\"10751147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MLP protein is present in the contractile protein fraction of cardiomyocytes, and its binding to myofibrils requires functional zinc finger (LIM) domains; MLP protein (but not mRNA) is decreased ~50% in failing human hearts, suggesting post-translational regulation.\",\n      \"method\": \"Western blot fractionation, domain mutagenesis, Northern blot, immunohistochemistry\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — fractionation with domain mutagenesis, single lab\",\n      \"pmids\": [\"10851202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MLP and ALP (a related PDZ-LIM protein) distribute to distinct subcellular compartments during myofibrillogenesis in cardiomyocytes: ALP co-distributes with alpha-actinin to Z-lines from the earliest stages, while MLP localizes to premyofibrils and nascent myofibrils before costamere establishment, suggesting MLP functions during differentiation prior to costamere formation.\",\n      \"method\": \"Immunofluorescence microscopy during myofibrillogenesis in cultured embryonic chick cardiomyocytes, GFP transfection, in vitro binding assay\",\n      \"journal\": \"Cell motility and the cytoskeleton\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with functional context, single lab\",\n      \"pmids\": [\"12589684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CSRP3 missense mutations cause hypertrophic cardiomyopathy (HCM); MLP is mainly a cytosolic component of cardiomyocytes (not tightly anchored to sarcomeric structures); at least one HCM-associated mutant form of MLP is destabilized in patient hearts.\",\n      \"method\": \"Linkage analysis, monoclonal antibody-based immunolocalization, in vitro and in vivo functional analysis of mutant MLP stability\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple families with segregating mutations, antibody localization, and functional destabilization data; strong evidence\",\n      \"pmids\": [\"18505755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The W4R (Trp4Arg) MLP variant causes reduced MLP mRNA and protein expression, weaker in vitro interaction of telethonin with W4R-MLP compared to wild-type MLP, and increased nuclear localization of W4R-MLP; knock-in mice develop age- and gene dosage-dependent hypertrophic cardiomyopathy.\",\n      \"method\": \"Knock-in mouse generation, in vitro binding assay (telethonin-MLP interaction), immunohistochemistry, Western blot\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knock-in animal model with multiple orthogonal methods including binding assay and localization\",\n      \"pmids\": [\"20044516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRP3/MLP expression in vascular smooth muscle cells is induced by mechanical stretch (not shear stress) during vein arterialization, identifying stretch as the primary biomechanical stimulus for CSRP3 induction in this context.\",\n      \"method\": \"Ex vivo flow-through system mimicking arterial conditions, in vivo rat vein arterialization model, quantitative RT-PCR, immunostaining\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and ex vivo models with controlled mechanical stimuli, single lab\",\n      \"pmids\": [\"19351738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MLP (CSRP3) contributes to correct autophagosome formation and flux in muscle cells by directly interacting with LC3, as demonstrated by co-immunoprecipitation and proximity ligation assay; MLP silencing results in decreased LC3-II, impaired degradation of long-lived proteins, and increased apoptotic susceptibility.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay (PLA), siRNA knockdown, Western blot, ultrastructural analysis\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus PLA for interaction, KD phenotype; single lab but two orthogonal interaction methods\",\n      \"pmids\": [\"27551448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Syndecan-4 directly binds MLP (CSRP3) with increased binding in heart failure; syndecan-4 mediates nuclear translocation of MLP in cardiomyocytes, as loss of syndecan-4 reduces nuclear MLP and overexpression increases it; a cell-permeable syndecan-4–MLP disruptor peptide reduces nuclear MLP levels.\",\n      \"method\": \"Affinity purification-MS interactome mapping, co-immunoprecipitation validation in HEK293 cells, nuclear fractionation of syndecan-4 knockout and overexpression models, disruptor peptide experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, nuclear fractionation with genetic and peptide perturbation, MS-based interactome; multiple orthogonal methods\",\n      \"pmids\": [\"30967474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MLP-deficient hESC-derived cardiomyocytes develop HCM-like phenotypes (enlarged cell size, disorganized sarcomere, mitochondrial damage) that progress to heart failure features; restoration of Ca2+ homeostasis with verapamil prevents these phenotypes, indicating that elevated intracellular Ca2+ is a central mechanistic consequence of MLP deficiency.\",\n      \"method\": \"CRISPR/Cas9 knockout of CSRP3 in hESCs, differentiation to cardiomyocytes, calcium imaging, pharmacological rescue with verapamil\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetic KO model with pharmacological rescue defining calcium handling as central mechanism\",\n      \"pmids\": [\"31406109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"S-nitrosylation of MLP at cysteine 79 (SNO-MLP) is elevated in hypertrophic myocardium and drives myocardial hypertrophy by promoting MLP binding to TLR3, which in turn increases TLR3–RIP3 complex formation and NLRP3 inflammasome activation; mutation of Cys79 or overexpression of GSNO reductase reduces hypertrophic growth.\",\n      \"method\": \"Biotin-switch assay for SNO detection, LC-MS/MS for SNO site identification, site-directed mutagenesis (C79 mutation), co-immunoprecipitation, siRNA knockdown of TLR3, TLR3 knockout mouse model, transverse aortic constriction model\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — SNO site identified by MS and confirmed by mutagenesis, downstream pathway confirmed by KO mouse and co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"31902237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of CSRP3 in chicken satellite cells inhibits myotube differentiation (but not proliferation) by upregulating TGF-β/Smad3 signaling, including increased Smad3 phosphorylation, identifying CSRP3 as a positive regulator of satellite cell differentiation acting upstream of TGF-β/Smad3.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blot for Smad3 phosphorylation, qRT-PCR, differentiation assays\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — KD/OE with pathway placement via phospho-Smad3, single lab, chicken model\",\n      \"pmids\": [\"30930226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CSRP3/MLP interacts with LC3 protein to promote autophagosome formation; CSRP3 silencing impairs autophagy (reduced ATG5, ATG7, LC3-II, Beclin-1) and increases apoptosis via caspase-3/9 cleavage in chicken myoblasts; autophagy activation rescues the apoptotic phenotype.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, Western blot, pharmacological autophagy activation rescue\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP for interaction, KD phenotype with rescue; single lab, avian model\",\n      \"pmids\": [\"31979369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Vitamin C promotes nuclear translocation of CSRP3, and nuclear CSRP3 interacts directly with myogenic transcription factors MyoD and MyoG to promote muscle differentiation and repair.\",\n      \"method\": \"Transcriptomics, proteomics, co-immunoprecipitation, nuclear translocation assays in C2C12 cells and mouse muscle injury model\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP demonstrating interaction with MyoD/MyoG, nuclear localization shown, single lab\",\n      \"pmids\": [\"35652451\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CSRP3/MLP is a dual-compartment LIM-only protein in striated muscle that maintains cardiomyocyte cytoarchitecture by linking actin filaments at costameres (via betaI-spectrin and alpha-actinin) and at the sarcomeric Z-line; it undergoes nuclear translocation (facilitated by syndecan-4) where it interacts with myogenic transcription factors, regulates autophagy through direct LC3 binding, and when S-nitrosylated at Cys79 recruits TLR3 to activate RIP3-NLRP3 inflammasome signaling, with loss-of-function or disease-causing missense mutations disrupting these interactions and leading to dilated or hypertrophic cardiomyopathy partly through dysregulation of calcium handling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CSRP3 (MLP) is a LIM-domain protein essential for striated muscle cytoarchitecture, mechanotransduction, and cardiomyocyte survival. At the cytoskeleton, CSRP3 links actin-based structures to the sarcolemma by binding βI-spectrin at costameres and α-actinin at Z-lines, and its loss causes dilated cardiomyopathy with disrupted myofibrillar organization and dysregulated calcium homeostasis that can be rescued by calcium channel blockade [PMID:9039266, PMID:10751147, PMID:31406109]. CSRP3 undergoes syndecan-4-dependent nuclear translocation where it interacts with myogenic transcription factors MyoD and MyoG to promote muscle differentiation, and in the cytoplasm it directly binds LC3 to support autophagosome formation, with its silencing impairing autophagic flux and increasing apoptosis [PMID:30967474, PMID:35652451, PMID:27551448]. Missense mutations in CSRP3 cause hypertrophic cardiomyopathy through protein destabilization and disrupted interactions, while S-nitrosylation at Cys79 in hypertrophic myocardium drives pathological signaling by recruiting TLR3 to activate the RIP3–NLRP3 inflammasome pathway [PMID:18505755, PMID:20044516, PMID:31902237].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that CSRP3 is required for cardiomyocyte cytoarchitecture answered the fundamental question of whether this LIM-domain protein has a structural role in terminally differentiated muscle, rather than being purely transcriptional.\",\n      \"evidence\": \"MLP knockout mice developing dilated cardiomyopathy with disrupted actin-based structures, ultrastructural and cardiac phenotyping\",\n      \"pmids\": [\"9039266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific molecular partners at the cytoskeleton not yet identified\", \"Whether the phenotype reflects a structural versus signaling defect was unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying βI-spectrin as a direct binding partner of the second LIM domain and demonstrating co-localization at costameres established CSRP3 as a physical linker between the spectrin membrane skeleton and the sarcomeric actin cytoskeleton.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding assays, confocal co-localization at sarcolemma overlying Z- and M-lines\",\n      \"pmids\": [\"10751147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CSRP3 bridges spectrin and α-actinin simultaneously was not tested\", \"Role at premyofibril versus mature costamere stages was unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Tracking CSRP3 localization during myofibrillogenesis revealed it acts at premyofibril and nascent myofibril stages before costamere formation, distinguishing its temporal role from that of the related PDZ-LIM protein ALP.\",\n      \"evidence\": \"Immunofluorescence during cardiomyocyte differentiation in embryonic chick cultures\",\n      \"pmids\": [\"12589684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether premyofibril localization is functionally required was not tested by perturbation\", \"Mammalian validation not performed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that CSRP3 missense mutations segregate with hypertrophic cardiomyopathy and that mutant protein is destabilized in patient hearts established CSRP3 as a bona fide HCM disease gene and showed that its predominant localization is cytosolic rather than tightly sarcomere-anchored.\",\n      \"evidence\": \"Linkage analysis in multiple families, monoclonal antibody immunolocalization, mutant protein stability assays\",\n      \"pmids\": [\"18505755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which destabilization leads to hypertrophy not defined\", \"Whether all HCM mutations act through destabilization versus altered interactions was unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The W4R knock-in mouse showed that a specific HCM-linked mutation weakens telethonin binding and increases nuclear MLP accumulation, establishing that disease mutations can alter both protein–protein interactions and subcellular distribution in a dosage- and age-dependent manner.\",\n      \"evidence\": \"Knock-in mice, in vitro telethonin–MLP binding assay, immunohistochemistry, Western blot\",\n      \"pmids\": [\"20044516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether increased nuclear MLP is pathogenic or compensatory was unclear\", \"The nuclear function of MLP remained undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that CSRP3 directly binds LC3 and is required for proper autophagosome formation revealed a previously unsuspected role in muscle autophagy, linking its loss to impaired protein turnover and increased apoptotic vulnerability.\",\n      \"evidence\": \"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown with autophagic flux measurements\",\n      \"pmids\": [\"27551448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The LC3-binding domain on CSRP3 was not mapped\", \"Whether autophagy impairment contributes to the cardiomyopathy phenotype in vivo was untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of syndecan-4 as a direct CSRP3 interactor that mediates its nuclear translocation resolved the long-standing question of how a predominantly cytoskeletal protein accesses the nucleus, and showed this interaction is enhanced in heart failure.\",\n      \"evidence\": \"Affinity purification-MS, reciprocal co-IP, nuclear fractionation in syndecan-4 KO/overexpression models, disruptor peptide\",\n      \"pmids\": [\"30967474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear targets of translocated MLP were not identified in this study\", \"Whether syndecan-4–MLP disruption is therapeutic in heart failure models was not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"CRISPR knockout of CSRP3 in human cardiomyocytes showed that elevated intracellular calcium is a central consequence of MLP loss, and pharmacological calcium normalization prevents HCM-like progression to heart failure, establishing calcium dysregulation as a unifying downstream mechanism.\",\n      \"evidence\": \"CSRP3 CRISPR KO in hESC-derived cardiomyocytes, calcium imaging, verapamil rescue\",\n      \"pmids\": [\"31406109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The molecular basis of calcium elevation (channel, SERCA, leak) was not defined\", \"Whether calcium normalization rescues in vivo models was untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of S-nitrosylation at Cys79 as a post-translational modification that converts CSRP3 into a pro-hypertrophic signaling molecule—by enabling TLR3 binding and RIP3–NLRP3 inflammasome activation—revealed a gain-of-function inflammatory mechanism distinct from loss-of-function structural roles.\",\n      \"evidence\": \"Biotin-switch assay, LC-MS/MS SNO-site mapping, C79 mutagenesis, TLR3 co-IP and KO mouse, transverse aortic constriction model\",\n      \"pmids\": [\"31902237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SNO-MLP-TLR3 axis operates in human heart failure tissue was not shown\", \"The nitrosylase/denitrosylase balance controlling Cys79 modification in vivo is unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that nuclear CSRP3 directly interacts with MyoD and MyoG identified transcription-factor partners and provided a molecular function for nuclear MLP in promoting myogenic differentiation and repair.\",\n      \"evidence\": \"Co-immunoprecipitation in C2C12 cells, nuclear translocation assays, mouse muscle injury model\",\n      \"pmids\": [\"35652451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CSRP3 acts as a co-activator or chromatin remodeler at myogenic promoters is unknown\", \"Genome-wide binding sites of CSRP3 have not been determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the cytoskeletal scaffolding, autophagy-promoting, and nuclear transcriptional co-regulatory functions of CSRP3 are coordinated in response to mechanical load, and which function is primarily disrupted in each cardiomyopathy-causing mutation, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of CSRP3 LIM domains bound to any partner exists\", \"The molecular basis of calcium dysregulation upon CSRP3 loss is not defined\", \"Whether autophagy impairment contributes to in vivo cardiomyopathy phenotypes is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 8, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 8, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 4, 5, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SPTBN1\",\n      \"ACTN2\",\n      \"SDC4\",\n      \"TCAP\",\n      \"MAP1LC3B\",\n      \"TLR3\",\n      \"MYOD1\",\n      \"MYOG\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}