{"gene":"LARP6","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2009,"finding":"LARP6 binds the conserved 5' stem-loop (5'SL) in the 5'UTR of type I collagen mRNAs (COL1A1 and COL1A2) in a sequence-specific manner with Kd of 1.4 nM, using a bipartite RNA binding domain (La motif + RRM). LARP6 does not associate with polysomes; overexpression blocks ribosomal loading on collagen mRNAs, while knockdown also decreases polysomal loading. LARP6 activity is required for focal (discrete ER-localized) synthesis of collagen polypeptides.","method":"RNA binding assay (Kd measurement), gel mobility shift, siRNA knockdown, polysome profiling, collagen-GFP reporter in cells","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding assay, polysome profiling, KD, reporter), replicated across multiple subsequent studies","pmids":["19917293"],"is_preprint":false},{"year":2014,"finding":"Structure of the La motif (LaM) and RRM1 of human LARP6 was solved, revealing considerable structural variation from the prototypic La protein. RNA recognition requires synergy between LaM, RRM1, and the interdomain linker. Mutagenesis guided by the structure showed that the interdomain linker and tandem domain dynamics are required for substrate selectivity toward the collagen 5'SL.","method":"X-ray crystallography, mutagenesis, NMR","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and multiple orthogonal structural/biochemical methods in one rigorous study","pmids":["25488812"],"is_preprint":false},{"year":2014,"finding":"Five specific nucleotides within the single-stranded regions of the 5'SL are required for high-affinity LARP6 binding; mutation of individual nucleotides abolishes binding. LARP6 requires both the La domain (T133 critical for folding) and the RRM (loop 3 critical for 5'SL binding). Loop 3 of the RRM also mediates interaction with the protein translocation channel SEC61, and a LARP6 mutant that binds 5'SL but cannot interact with SEC61 suppresses collagen synthesis in a dominant-negative manner.","method":"Gel mobility shift assay, mutagenesis, Co-IP (LARP6–SEC61 interaction), dominant-negative overexpression","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis defining binding residues plus Co-IP and dominant-negative functional validation in single lab with multiple orthogonal methods","pmids":["25692237"],"is_preprint":false},{"year":2014,"finding":"LARP6 associates with ER membranes and, together with nonmuscle myosin filaments, partitions collagen mRNAs to the ER membrane prior to signal peptide synthesis. Knockdown of LARP6 or depolymerization of nonmuscle myosin releases collagen mRNAs from the ER membrane and causes hypermodification, poor secretion, and cytosolic accumulation of collagen polypeptides, indicating loss of coordinated translation.","method":"ER membrane fractionation, siRNA knockdown, nonmuscle myosin depolymerization, Western blot, microscopy","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation with functional consequence (collagen hypermodification/secretion defect), two orthogonal perturbations (siRNA + drug), single lab","pmids":["25271881"],"is_preprint":false},{"year":2013,"finding":"FKBP3 (FKBP25) interacts with LARP6 and co-immunoprecipitates collagen mRNAs. FK506 (tacrolimus) weakens the FKBP3–LARP6 interaction, reducing pull-down of collagen mRNAs by FKBP3 and inhibiting translation of collagen α1(I) polypeptide without affecting collagen mRNA levels.","method":"Co-IP, Western blot, FK506 pharmacological treatment, in vitro collagen synthesis assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP of endogenous proteins with pharmacological perturbation, single lab, two orthogonal methods","pmids":["23755290"],"is_preprint":false},{"year":2016,"finding":"LARP6 is phosphorylated at 8 serines in lung fibroblasts; phosphorylation follows a hierarchical order with S451 as a prerequisite for other phosphorylations. PI3K/Akt pathway (specifically Akt kinase) phosphorylates S451. S451A mutant has a dominant-negative effect on collagen biosynthesis, drastically reducing collagen secretion and inducing hypermodification of collagen α2(I) polypeptides.","method":"Mass spectrometry phosphosite mapping, PI3K/Akt inhibition, site-directed mutagenesis (S451A dominant negative), collagen secretion assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS phosphosite mapping plus kinase inhibition plus mutagenesis with functional readout, multiple orthogonal methods, single lab","pmids":["26932461"],"is_preprint":false},{"year":2017,"finding":"mTORC1 phosphorylates LARP6 on S348 and S409. The S348A/S409A mutant acts as a dominant-negative in collagen biosynthesis, retarding secretion and causing excessive posttranslational modifications. S348A/S409A weakly interacts with accessory protein STRAP (needed for coordinated translation); mTORC1 inhibitor rapamycin or raptor knockdown attenuates this interaction. Loss of S348/S409 phosphorylation also sequesters LARP6 at the ER membrane.","method":"Site-directed mutagenesis, rapamycin treatment, raptor siRNA knockdown, Co-IP (LARP6–STRAP), collagen secretion assay, ER fractionation","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis plus pharmacological and genetic mTORC1 inhibition plus Co-IP with functional readout, multiple orthogonal methods, single lab","pmids":["28112218"],"is_preprint":false},{"year":2021,"finding":"The La domain of LARP6 is necessary and sufficient for sequence-specific recognition of the 5'SL RNA. A three-amino-acid RNK motif in the flexible loop connecting the second α-helix to the β-sheet of the La domain is critical for binding; mutation of any of these three residues abolishes binding. The RRM domain stabilizes the La domain–5'SL complex but does not make extensive contacts with 5'SL. The major UV crosslinking site of LARP6 to 5'SL RNA maps to this RNK motif. The RNK motif is absent in other LARPs, which cannot bind 5'SL.","method":"Mutagenesis, gel mobility shift, UV crosslinking, domain deletion analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assays with mutagenesis and UV crosslinking, multiple orthogonal methods, single lab","pmids":["34896113"],"is_preprint":false},{"year":2021,"finding":"ER-anchored CRTH2 (trafficked to ER membrane in a caveolin-1-dependent manner) binds the collagen mRNA recognition motif of LARP6, promoting degradation of collagen mRNA in fibroblasts. CRTH2 deficiency increases collagen biosynthesis, and this effect is rescued by LARP6 depletion, placing CRTH2 upstream of LARP6 in collagen mRNA regulation.","method":"Co-IP (CRTH2–LARP6 interaction), caveolin-1 KO (trafficking), genetic epistasis (CRTH2 KO + LARP6 KD rescue), collagen mRNA stability assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, genetic epistasis with rescue, multiple orthogonal methods including in vivo fibrosis model, single lab","pmids":["34223653"],"is_preprint":false},{"year":2023,"finding":"LARP6 binds ZNF267 mRNA and regulates its stability and translation. This leads to inhibition of SGMS2 (a downstream target of ZNF267), causing ceramide/sphingomyelin imbalance in colorectal cancer cells. LARP6 also enhances autophagy activity in CRC cells, at least partially through inhibition of SGMS2-mediated sphingomyelin synthesis.","method":"RIP-seq, RIP-qPCR, LARP6 overexpression/knockdown, Western blot, autophagy assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP-seq plus functional knockdown/overexpression with downstream pathway readouts, single lab","pmids":["36691044"],"is_preprint":false},{"year":2024,"finding":"In Xenopus multiciliated cells, LARP6 and DNAAF6 colocalize in biomolecular condensates (dynein axonemal particles). LARP6 binds tubulin alpha 1c-like mRNA encoding α-tubulin (a major component of ciliary axoneme). DNAAF6 is required for high α-tubulin protein expression near the apical side during ciliogenesis, and a DNAAF6 mutant that cannot bind LARP6 fails to restore apical α-tubulin expression, demonstrating that the LARP6–DNAAF6 interaction is required for ciliogenesis.","method":"Co-IP (LARP6–DNAAF6), live imaging/colocalization in condensates, Xenopus morphant/rescue experiments, mutagenesis of DNAAF6 binding interface","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, morphant rescue with binding-deficient mutant, single lab, Xenopus model organism","pmids":["38762183"],"is_preprint":false},{"year":2026,"finding":"eCLIP and ribosome profiling in human hepatic stellate cells showed that LARP6 interacts with mature mRNAs of >300 genes, binding RNA structural elements within COL1A1, COL1A2, and COL3A1 to regulate mRNA expression and translation. IP-mass spectrometry identified LARP6 protein-protein interactions with mRNA translation components and the actin cytoskeleton. JUNB transcription factor upregulates LARP6 expression in activated HSCs.","method":"eCLIP, ribosome profiling, IP-mass spectrometry, snRNA-seq, ATAC-seq, siRNA knockdown","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — eCLIP + ribosome profiling + IP-MS, multiple orthogonal genome-wide methods with functional validation, peer-reviewed","pmids":["41746718"],"is_preprint":false},{"year":2026,"finding":"The N-terminal intrinsically disordered region (IDR) of LARP6 restricts the conformational flexibility of the adjacent La-module and forms auxiliary contacts with RNA, thereby narrowing LARP6 RNA-binding selectivity. Deletion of the N-terminal IDR broadens LARP6 RNA footprints (detected by iCLIP). IDR-mediated RNA-binding selectivity is critical for LARP6-driven cancer cell viability and invasion. The La-module (not IDRs) is essential for RNA binding per se.","method":"Mass spectrometry-based RNA interaction mapping in living cells, iCLIP, mutagenesis/deletion analysis, cancer cell viability and invasion assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — iCLIP with mutagenesis plus MS-based RNA interaction mapping plus functional cancer cell assays, multiple orthogonal methods, single lab","pmids":["41714637"],"is_preprint":false},{"year":2009,"finding":"Acheron/LARP6 acts upstream of the muscle-specific transcription factor MyoD in C2C12 myoblasts. Forced expression of ectopic Acheron results in larger myotubes and reserve cell death; dominant-negative or antisense Acheron blocks myotube formation. In zebrafish, antisense morpholino reduction of Acheron leads to muscle fiber loss, while ectopic Acheron enhances muscle fiber formation.","method":"C2C12 myoblast differentiation assay, ectopic expression, dominant-negative expression, antisense knockdown, zebrafish morpholino","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis (upstream of MyoD) established by dominant-negative and antisense experiments in two model systems, single lab","pmids":["19481601"],"is_preprint":false},{"year":2009,"finding":"Acheron/LARP6 controls expression of the laminin receptor integrin α7β1 during myoblast differentiation; loss of Acheron (via antisense or deletion mutant) blocks laminin receptor expression and reduces substrate adhesion and migration on laminin but not fibronectin, linking Acheron to integrin-mediated extracellular matrix interactions during myogenesis.","method":"Ectopic expression, antisense/dominant-negative deletion mutant, integrin expression (Western blot/flow cytometry), adhesion and migration assays","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with specific integrin expression and functional readouts, single lab","pmids":["19889961"],"is_preprint":false},{"year":2011,"finding":"In human breast cancer MDA-MB-231 cells, Acheron/LARP6 enhances cell proliferation, lamellipodia formation, invasive activity, and drives elevated expression of MMP-9 and VEGF. Nuclear localization is required: AchnNLS (lacking NLS) did not enhance these activities, while AchnNES (lacking NES, thus retained in nucleus) did, indicating that nuclear localization is necessary for Acheron's pro-tumorigenic activity.","method":"Stable expression of GFP-tagged Acheron variants (WT, ΔNLS, ΔNES), proliferation assay, invasion assay, in vivo xenograft (SCID/Beige mice), Western blot for MMP-9/VEGF","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — NLS/NES deletion mutants establish localization requirement, multiple functional readouts in vitro and in vivo, single lab","pmids":["21387291"],"is_preprint":false},{"year":2020,"finding":"In Manduca sexta ISMs, Acheron/LARP6 functions as a survival protein protecting muscles until eclosion; at eclosion it becomes phosphorylated and degraded in response to Eclosion Hormone (EH). Acheron binds a novel BH3-only protein BBH1 (BAD/BNIP3 homology 1); BBH1 accumulates when muscles commit to die and is presumably liberated upon Acheron degradation, correlated with cytochrome c release and cell death. RNAi in Drosophila confirmed loss of Acheron causes precocious muscle death.","method":"Co-IP (Acheron–BBH1), phosphorylation assay (EH-stimulated), RNAi in Drosophila, cytochrome c release assay","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identifying novel binding partner BBH1, RNAi epistasis in Drosophila, multiple model organisms, single lab","pmids":["32850788"],"is_preprint":false},{"year":2025,"finding":"De novo solution NMR structure of the La domain of human LARP6 in complex with 5'SL RNA reveals a non-canonical binding interface integrating electrostatic and hydrophobic contacts with shape complementarity. Chemical shift perturbation, solvent paramagnetic relaxation enhancement, intermolecular NOEs, and targeted mutagenesis converge on this interface. The La domain alone discriminates 5'SL from homopolymeric or purely helical hairpin RNAs with low-nanomolar affinity, overturning the view that the RRM is required for recognition.","method":"Solution NMR structure determination, chemical shift perturbation, paramagnetic relaxation enhancement, intermolecular NOEs, mutagenesis, RNA binding affinity measurements","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with multiple orthogonal NMR methods plus mutagenesis validation, single lab, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.05.22.652967"],"is_preprint":true},{"year":2025,"finding":"The La domain of LARP6 is stabilized >50-fold when in complex with its cognate 5'SL RNA compared to the unbound (aggregation-prone) state. C-terminal truncations greatly impair protein stability while N-terminal truncations have little effect on aggregation or RNA binding.","method":"Recombinant protein expression, limited proteolysis, stability assays, RNA binding assays","journal":"ACS omega","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro biochemical characterization with multiple construct variants, single lab, published peer-reviewed","pmids":["40191362"],"is_preprint":false},{"year":2025,"finding":"LARP6 regulates alternative splicing of >1000 events in MDA-MB-231 TNBC cells and tends to bind the CGACGAG motif. iRIP-seq identified 16 genes where LARP6 directly binds and regulates alternative splicing, with enrichment in DNA repair and cell cycle pathways.","method":"RNA-seq, iRIP-seq, RT-qPCR, RIP-qPCR","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — iRIP-seq with RT-qPCR validation, single lab, single method class","pmids":["40050364"],"is_preprint":false}],"current_model":"LARP6 is an RNA-binding protein that uses its La-module (La domain + RRM1) and flanking intrinsically disordered regions to bind with low-nanomolar affinity and sequence specificity to a conserved 5' stem-loop (5'SL) in the 5'UTR of type I and III collagen mRNAs; the La domain RNK motif mediates initial 5'SL recognition while the RRM stabilizes the complex and contacts the SEC61 translocon to direct collagen mRNAs to ER membrane for coordinated translation; LARP6 activity is regulated by hierarchical phosphorylation (Akt phosphorylates S451; mTORC1 phosphorylates S348/S409, which promotes interaction with accessory protein STRAP for coordinated collagen mRNA translation and LARP6 recycling from the ER); LARP6 also binds interacting partners including FKBP3 and DNAAF6, acts upstream of MyoD in myogenesis, and broadly regulates the translation and alternative splicing of hundreds of mRNAs beyond collagen, including through binding ZNF267 mRNA to modulate sphingomyelin metabolism in cancer cells."},"narrative":{"mechanistic_narrative":"LARP6 is a sequence-specific RNA-binding protein that licenses the coordinated translation of fibrillar collagen mRNAs and, more broadly, sculpts the translation and splicing of hundreds of transcripts [PMID:19917293, PMID:41746718]. It recognizes a conserved 5' stem-loop (5'SL) in the 5'UTR of type I and III collagen mRNAs (COL1A1, COL1A2, COL3A1) with low-nanomolar affinity through a bipartite La-module; the La domain is necessary and sufficient for 5'SL recognition via a three-residue RNK motif in a flexible loop, while the RRM stabilizes the complex, with interdomain dynamics and an N-terminal intrinsically disordered region restricting conformational flexibility to narrow binding selectivity [PMID:19917293, PMID:25488812, PMID:34896113, PMID:41714637, PMID:bio_10.1101_2025.05.22.652967]. Through a SEC61-contacting loop in its RRM, LARP6 directs collagen mRNAs to the ER membrane, where together with nonmuscle myosin filaments it partitions them for focal, coordinated translation; disrupting this targeting causes hypermodification, poor secretion, and cytosolic accumulation of collagen [PMID:25692237, PMID:25271881]. LARP6 activity is governed by hierarchical phosphorylation: Akt phosphorylates S451 as a prerequisite for further modification, and mTORC1 phosphorylates S348/S409 to promote interaction with the accessory protein STRAP and release LARP6 from the ER, with phospho-deficient mutants acting dominant-negatively on collagen biosynthesis [PMID:26932461, PMID:28112218]. Additional partners FKBP3, the ER-anchored CRTH2 (which routes collagen mRNA to degradation), and DNAAF6 (which co-condenses with LARP6 to support α-tubulin expression during ciliogenesis) modulate or extend these activities [PMID:23755290, PMID:34223653, PMID:38762183]. Beyond collagen, LARP6 binds ZNF267 mRNA to perturb SGMS2-dependent sphingomyelin metabolism and autophagy in colorectal cancer, regulates >1000 alternative splicing events enriched in DNA repair and cell cycle genes, and its IDR-dependent RNA selectivity drives cancer cell viability and invasion [PMID:36691044, PMID:41714637, PMID:40050364]. In development, LARP6 (Acheron) acts upstream of MyoD and integrin α7β1 during myogenesis and functions as a muscle survival factor in insects [PMID:19481601, PMID:19889961, PMID:32850788].","teleology":[{"year":2009,"claim":"Established LARP6 as a sequence-specific regulator of collagen biosynthesis, answering whether a dedicated factor controls type I collagen mRNA translation.","evidence":"RNA binding/Kd measurement, gel shift, siRNA knockdown, polysome profiling and collagen-GFP reporter in cells","pmids":["19917293"],"confidence":"High","gaps":["Structural basis of bipartite binding undefined","Mechanism coupling binding to focal ER synthesis not resolved"]},{"year":2009,"claim":"Independently identified LARP6 (Acheron) as a developmental regulator acting upstream of MyoD and integrin α7β1 in myogenesis, broadening its biological scope beyond collagen.","evidence":"C2C12 differentiation, dominant-negative/antisense, zebrafish morpholino, integrin expression and adhesion/migration assays","pmids":["19481601","19889961"],"confidence":"Medium","gaps":["Molecular link between LARP6 RNA binding and MyoD regulation unknown","Direct target mRNAs in myogenesis not identified"]},{"year":2011,"claim":"Showed nuclear-localized Acheron/LARP6 promotes proliferation and invasion in breast cancer, implicating it in tumorigenesis.","evidence":"NLS/NES deletion mutants, proliferation/invasion assays, xenografts, MMP-9/VEGF Western blot","pmids":["21387291"],"confidence":"Medium","gaps":["Nuclear molecular targets not defined","Relationship to cytoplasmic collagen-regulatory function unclear"]},{"year":2013,"claim":"Identified FKBP3 as a LARP6 partner required for collagen polypeptide translation, adding an accessory factor to the collagen translation machinery.","evidence":"Co-IP, FK506 perturbation, in vitro collagen synthesis assay","pmids":["23755290"],"confidence":"Medium","gaps":["Mechanism of FKBP3 contribution to translation unresolved","Single lab, no reciprocal structural validation"]},{"year":2014,"claim":"Defined the structural and sequence determinants of 5'SL recognition and linked LARP6 to the SEC61 translocon, explaining how it couples mRNA binding to ER-targeted collagen synthesis.","evidence":"X-ray crystallography/NMR of La-module, mutagenesis, gel shift, Co-IP with SEC61, dominant-negative overexpression, ER fractionation with nonmuscle myosin perturbation","pmids":["25488812","25692237","25271881"],"confidence":"High","gaps":["Atomic structure of the La-domain–5'SL complex still missing","How myosin filaments physically partition mRNAs unclear"]},{"year":2017,"claim":"Revealed hierarchical Akt and mTORC1 phosphorylation as the regulatory switch controlling LARP6 function and ER recycling via STRAP.","evidence":"MS phosphosite mapping, kinase inhibition, site-directed mutagenesis with dominant-negative readouts, Co-IP with STRAP, ER fractionation","pmids":["26932461","28112218"],"confidence":"High","gaps":["Order and stoichiometry of all 8 phosphosites incomplete","STRAP's mechanistic role in coordinated translation undefined"]},{"year":2021,"claim":"Pinpointed the La-domain RNK motif as the necessary and sufficient determinant of 5'SL specificity and identified CRTH2 as an upstream negative regulator of collagen mRNA stability.","evidence":"Mutagenesis, UV crosslinking, domain deletion; reciprocal Co-IP, caveolin-1 KO, genetic epistasis with rescue","pmids":["34896113","34223653"],"confidence":"High","gaps":["Structural detail of RNK–RNA contact not yet atomic","How CRTH2 routes bound mRNA to degradation unknown"]},{"year":2023,"claim":"Extended LARP6 targets beyond collagen to ZNF267 mRNA, linking it to sphingomyelin metabolism and autophagy in colorectal cancer.","evidence":"RIP-seq/RIP-qPCR, overexpression/knockdown, Western blot, autophagy assays","pmids":["36691044"],"confidence":"Medium","gaps":["Direct vs indirect regulation of SGMS2 not separated","Whether 5'SL-like elements mediate ZNF267 binding unknown"]},{"year":2024,"claim":"Demonstrated that LARP6–DNAAF6 condensates drive α-tubulin mRNA expression for ciliogenesis, defining a distinct condensate-based function.","evidence":"Co-IP, live colocalization imaging, Xenopus morphant/rescue with binding-deficient DNAAF6 mutant","pmids":["38762183"],"confidence":"Medium","gaps":["Whether condensate formation is required for translation control untested","Conservation in mammalian ciliogenesis not shown"]},{"year":2026,"claim":"Genome-wide profiling redefined LARP6 as a broad RNA regulator binding >300 mature mRNAs and over a thousand splicing events, with an IDR that narrows its RNA selectivity to support cancer phenotypes.","evidence":"eCLIP, ribosome profiling, IP-MS, iCLIP, iRIP-seq, mutagenesis, cancer cell viability/invasion and splicing assays","pmids":["41746718","41714637","40050364"],"confidence":"High","gaps":["Functional consequence of most bound transcripts not validated","Coupling between IDR-restricted binding and specific splicing/translation outcomes incomplete"]},{"year":2025,"claim":"Solution structure and stability studies of the La domain–5'SL complex showed the La domain alone discriminates 5'SL with low-nanomolar affinity and is stabilized >50-fold upon binding.","evidence":"Solution NMR structure (preprint), CSP/PRE/NOEs, mutagenesis; limited proteolysis and stability assays with truncations","pmids":["bio_10.1101_2025.05.22.652967","40191362"],"confidence":"High","gaps":["NMR structure awaits peer review","Role of full-length protein and RRM in vivo selectivity vs isolated La domain not reconciled"]},{"year":null,"claim":"How LARP6's discrete activities—ER-coupled collagen translation, condensate-based ciliogenesis, nuclear pro-tumorigenic signaling, and genome-wide splicing—are integrated under a single regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking phosphorylation state to target choice","Functional significance of most non-collagen targets unvalidated","Mammalian relevance of model-organism developmental roles untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,7,11,12,17,19]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,3,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,3,6,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,11]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,3,11]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[11,19]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,3,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13,14,10]}],"complexes":["dynein axonemal particle (LARP6–DNAAF6 condensate)"],"partners":["SEC61","STRAP","FKBP3","CRTH2","DNAAF6","BBH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BRS8","full_name":"La-related protein 6","aliases":["Acheron","Achn","La ribonucleoprotein domain family member 6"],"length_aa":491,"mass_kda":54.7,"function":"Regulates the coordinated translation of type I collagen alpha-1 and alpha-2 mRNAs, CO1A1 and CO1A2. Stabilizes mRNAs through high-affinity binding of a stem-loop structure in their 5' UTR. This regulation requires VIM and MYH10 filaments, and the helicase DHX9","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BRS8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LARP6","classification":"Not Classified","n_dependent_lines":45,"n_total_lines":1208,"dependency_fraction":0.037251655629139076},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LARP6","total_profiled":1310},"omim":[{"mim_id":"618657","title":"La RIBONUCLEOPROTEIN 4; LARP4","url":"https://www.omim.org/entry/618657"},{"mim_id":"612026","title":"La RIBONUCLEOPROTEIN 7, TRANSCRIPTIONAL REGULATOR; LARP7","url":"https://www.omim.org/entry/612026"},{"mim_id":"611300","title":"La RIBONUCLEOPROTEIN 6, TRANSLATIONAL REGULATOR; LARP6","url":"https://www.omim.org/entry/611300"},{"mim_id":"609159","title":"NODAL MODULATOR 3; NOMO3","url":"https://www.omim.org/entry/609159"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":123.6}],"url":"https://www.proteinatlas.org/search/LARP6"},"hgnc":{"alias_symbol":["acheron","FLJ11196"],"prev_symbol":[]},"alphafold":{"accession":"Q9BRS8","domains":[{"cath_id":"1.10.10.10","chopping":"89-168","consensus_level":"high","plddt":90.4305,"start":89,"end":168},{"cath_id":"3.30.70.330","chopping":"184-289","consensus_level":"high","plddt":71.9516,"start":184,"end":289}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRS8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRS8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRS8-F1-predicted_aligned_error_v6.png","plddt_mean":60.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LARP6","jax_strain_url":"https://www.jax.org/strain/search?query=LARP6"},"sequence":{"accession":"Q9BRS8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BRS8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BRS8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRS8"}},"corpus_meta":[{"pmid":"19917293","id":"PMC_19917293","title":"Binding of LARP6 to the conserved 5' stem-loop regulates translation of mRNAs encoding type I collagen.","date":"2009","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19917293","citation_count":92,"is_preprint":false},{"pmid":"24469459","id":"PMC_24469459","title":"Insulin-like growth factor-1 increases synthesis of collagen type I via induction of the mRNA-binding protein LARP6 expression and binding to the 5' stem-loop of COL1a1 and COL1a2 mRNA.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24469459","citation_count":84,"is_preprint":false},{"pmid":"27011170","id":"PMC_27011170","title":"LARP6 Meets Collagen mRNA: Specific Regulation of Type I Collagen Expression.","date":"2016","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27011170","citation_count":77,"is_preprint":false},{"pmid":"25488812","id":"PMC_25488812","title":"Synergic interplay of the La motif, RRM1 and the interdomain linker of LARP6 in the recognition of collagen mRNA expands the RNA binding repertoire of the La module.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25488812","citation_count":56,"is_preprint":false},{"pmid":"30674965","id":"PMC_30674965","title":"Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30674965","citation_count":40,"is_preprint":false},{"pmid":"25692237","id":"PMC_25692237","title":"Characterization of binding of LARP6 to the 5' stem-loop of collagen mRNAs: implications for synthesis of type I collagen.","date":"2014","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/25692237","citation_count":37,"is_preprint":false},{"pmid":"17383118","id":"PMC_17383118","title":"Acheron, a novel member of the Lupus Antigen family, is induced during the programmed cell death of skeletal muscles in the moth Manduca sexta.","date":"2007","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/17383118","citation_count":34,"is_preprint":false},{"pmid":"26932461","id":"PMC_26932461","title":"Akt mediated phosphorylation of LARP6; 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LARP6 does not associate with polysomes; overexpression blocks ribosomal loading on collagen mRNAs, while knockdown also decreases polysomal loading. LARP6 activity is required for focal (discrete ER-localized) synthesis of collagen polypeptides.\",\n      \"method\": \"RNA binding assay (Kd measurement), gel mobility shift, siRNA knockdown, polysome profiling, collagen-GFP reporter in cells\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding assay, polysome profiling, KD, reporter), replicated across multiple subsequent studies\",\n      \"pmids\": [\"19917293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Structure of the La motif (LaM) and RRM1 of human LARP6 was solved, revealing considerable structural variation from the prototypic La protein. RNA recognition requires synergy between LaM, RRM1, and the interdomain linker. Mutagenesis guided by the structure showed that the interdomain linker and tandem domain dynamics are required for substrate selectivity toward the collagen 5'SL.\",\n      \"method\": \"X-ray crystallography, mutagenesis, NMR\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and multiple orthogonal structural/biochemical methods in one rigorous study\",\n      \"pmids\": [\"25488812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Five specific nucleotides within the single-stranded regions of the 5'SL are required for high-affinity LARP6 binding; mutation of individual nucleotides abolishes binding. LARP6 requires both the La domain (T133 critical for folding) and the RRM (loop 3 critical for 5'SL binding). Loop 3 of the RRM also mediates interaction with the protein translocation channel SEC61, and a LARP6 mutant that binds 5'SL but cannot interact with SEC61 suppresses collagen synthesis in a dominant-negative manner.\",\n      \"method\": \"Gel mobility shift assay, mutagenesis, Co-IP (LARP6–SEC61 interaction), dominant-negative overexpression\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis defining binding residues plus Co-IP and dominant-negative functional validation in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25692237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LARP6 associates with ER membranes and, together with nonmuscle myosin filaments, partitions collagen mRNAs to the ER membrane prior to signal peptide synthesis. Knockdown of LARP6 or depolymerization of nonmuscle myosin releases collagen mRNAs from the ER membrane and causes hypermodification, poor secretion, and cytosolic accumulation of collagen polypeptides, indicating loss of coordinated translation.\",\n      \"method\": \"ER membrane fractionation, siRNA knockdown, nonmuscle myosin depolymerization, Western blot, microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation with functional consequence (collagen hypermodification/secretion defect), two orthogonal perturbations (siRNA + drug), single lab\",\n      \"pmids\": [\"25271881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FKBP3 (FKBP25) interacts with LARP6 and co-immunoprecipitates collagen mRNAs. FK506 (tacrolimus) weakens the FKBP3–LARP6 interaction, reducing pull-down of collagen mRNAs by FKBP3 and inhibiting translation of collagen α1(I) polypeptide without affecting collagen mRNA levels.\",\n      \"method\": \"Co-IP, Western blot, FK506 pharmacological treatment, in vitro collagen synthesis assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP of endogenous proteins with pharmacological perturbation, single lab, two orthogonal methods\",\n      \"pmids\": [\"23755290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LARP6 is phosphorylated at 8 serines in lung fibroblasts; phosphorylation follows a hierarchical order with S451 as a prerequisite for other phosphorylations. PI3K/Akt pathway (specifically Akt kinase) phosphorylates S451. S451A mutant has a dominant-negative effect on collagen biosynthesis, drastically reducing collagen secretion and inducing hypermodification of collagen α2(I) polypeptides.\",\n      \"method\": \"Mass spectrometry phosphosite mapping, PI3K/Akt inhibition, site-directed mutagenesis (S451A dominant negative), collagen secretion assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS phosphosite mapping plus kinase inhibition plus mutagenesis with functional readout, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"26932461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"mTORC1 phosphorylates LARP6 on S348 and S409. The S348A/S409A mutant acts as a dominant-negative in collagen biosynthesis, retarding secretion and causing excessive posttranslational modifications. S348A/S409A weakly interacts with accessory protein STRAP (needed for coordinated translation); mTORC1 inhibitor rapamycin or raptor knockdown attenuates this interaction. Loss of S348/S409 phosphorylation also sequesters LARP6 at the ER membrane.\",\n      \"method\": \"Site-directed mutagenesis, rapamycin treatment, raptor siRNA knockdown, Co-IP (LARP6–STRAP), collagen secretion assay, ER fractionation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis plus pharmacological and genetic mTORC1 inhibition plus Co-IP with functional readout, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"28112218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The La domain of LARP6 is necessary and sufficient for sequence-specific recognition of the 5'SL RNA. A three-amino-acid RNK motif in the flexible loop connecting the second α-helix to the β-sheet of the La domain is critical for binding; mutation of any of these three residues abolishes binding. The RRM domain stabilizes the La domain–5'SL complex but does not make extensive contacts with 5'SL. The major UV crosslinking site of LARP6 to 5'SL RNA maps to this RNK motif. The RNK motif is absent in other LARPs, which cannot bind 5'SL.\",\n      \"method\": \"Mutagenesis, gel mobility shift, UV crosslinking, domain deletion analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assays with mutagenesis and UV crosslinking, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34896113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ER-anchored CRTH2 (trafficked to ER membrane in a caveolin-1-dependent manner) binds the collagen mRNA recognition motif of LARP6, promoting degradation of collagen mRNA in fibroblasts. CRTH2 deficiency increases collagen biosynthesis, and this effect is rescued by LARP6 depletion, placing CRTH2 upstream of LARP6 in collagen mRNA regulation.\",\n      \"method\": \"Co-IP (CRTH2–LARP6 interaction), caveolin-1 KO (trafficking), genetic epistasis (CRTH2 KO + LARP6 KD rescue), collagen mRNA stability assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, genetic epistasis with rescue, multiple orthogonal methods including in vivo fibrosis model, single lab\",\n      \"pmids\": [\"34223653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LARP6 binds ZNF267 mRNA and regulates its stability and translation. This leads to inhibition of SGMS2 (a downstream target of ZNF267), causing ceramide/sphingomyelin imbalance in colorectal cancer cells. LARP6 also enhances autophagy activity in CRC cells, at least partially through inhibition of SGMS2-mediated sphingomyelin synthesis.\",\n      \"method\": \"RIP-seq, RIP-qPCR, LARP6 overexpression/knockdown, Western blot, autophagy assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP-seq plus functional knockdown/overexpression with downstream pathway readouts, single lab\",\n      \"pmids\": [\"36691044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Xenopus multiciliated cells, LARP6 and DNAAF6 colocalize in biomolecular condensates (dynein axonemal particles). LARP6 binds tubulin alpha 1c-like mRNA encoding α-tubulin (a major component of ciliary axoneme). DNAAF6 is required for high α-tubulin protein expression near the apical side during ciliogenesis, and a DNAAF6 mutant that cannot bind LARP6 fails to restore apical α-tubulin expression, demonstrating that the LARP6–DNAAF6 interaction is required for ciliogenesis.\",\n      \"method\": \"Co-IP (LARP6–DNAAF6), live imaging/colocalization in condensates, Xenopus morphant/rescue experiments, mutagenesis of DNAAF6 binding interface\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, morphant rescue with binding-deficient mutant, single lab, Xenopus model organism\",\n      \"pmids\": [\"38762183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"eCLIP and ribosome profiling in human hepatic stellate cells showed that LARP6 interacts with mature mRNAs of >300 genes, binding RNA structural elements within COL1A1, COL1A2, and COL3A1 to regulate mRNA expression and translation. IP-mass spectrometry identified LARP6 protein-protein interactions with mRNA translation components and the actin cytoskeleton. JUNB transcription factor upregulates LARP6 expression in activated HSCs.\",\n      \"method\": \"eCLIP, ribosome profiling, IP-mass spectrometry, snRNA-seq, ATAC-seq, siRNA knockdown\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — eCLIP + ribosome profiling + IP-MS, multiple orthogonal genome-wide methods with functional validation, peer-reviewed\",\n      \"pmids\": [\"41746718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The N-terminal intrinsically disordered region (IDR) of LARP6 restricts the conformational flexibility of the adjacent La-module and forms auxiliary contacts with RNA, thereby narrowing LARP6 RNA-binding selectivity. Deletion of the N-terminal IDR broadens LARP6 RNA footprints (detected by iCLIP). IDR-mediated RNA-binding selectivity is critical for LARP6-driven cancer cell viability and invasion. The La-module (not IDRs) is essential for RNA binding per se.\",\n      \"method\": \"Mass spectrometry-based RNA interaction mapping in living cells, iCLIP, mutagenesis/deletion analysis, cancer cell viability and invasion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — iCLIP with mutagenesis plus MS-based RNA interaction mapping plus functional cancer cell assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41714637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Acheron/LARP6 acts upstream of the muscle-specific transcription factor MyoD in C2C12 myoblasts. Forced expression of ectopic Acheron results in larger myotubes and reserve cell death; dominant-negative or antisense Acheron blocks myotube formation. In zebrafish, antisense morpholino reduction of Acheron leads to muscle fiber loss, while ectopic Acheron enhances muscle fiber formation.\",\n      \"method\": \"C2C12 myoblast differentiation assay, ectopic expression, dominant-negative expression, antisense knockdown, zebrafish morpholino\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis (upstream of MyoD) established by dominant-negative and antisense experiments in two model systems, single lab\",\n      \"pmids\": [\"19481601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Acheron/LARP6 controls expression of the laminin receptor integrin α7β1 during myoblast differentiation; loss of Acheron (via antisense or deletion mutant) blocks laminin receptor expression and reduces substrate adhesion and migration on laminin but not fibronectin, linking Acheron to integrin-mediated extracellular matrix interactions during myogenesis.\",\n      \"method\": \"Ectopic expression, antisense/dominant-negative deletion mutant, integrin expression (Western blot/flow cytometry), adhesion and migration assays\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with specific integrin expression and functional readouts, single lab\",\n      \"pmids\": [\"19889961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In human breast cancer MDA-MB-231 cells, Acheron/LARP6 enhances cell proliferation, lamellipodia formation, invasive activity, and drives elevated expression of MMP-9 and VEGF. Nuclear localization is required: AchnNLS (lacking NLS) did not enhance these activities, while AchnNES (lacking NES, thus retained in nucleus) did, indicating that nuclear localization is necessary for Acheron's pro-tumorigenic activity.\",\n      \"method\": \"Stable expression of GFP-tagged Acheron variants (WT, ΔNLS, ΔNES), proliferation assay, invasion assay, in vivo xenograft (SCID/Beige mice), Western blot for MMP-9/VEGF\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — NLS/NES deletion mutants establish localization requirement, multiple functional readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"21387291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Manduca sexta ISMs, Acheron/LARP6 functions as a survival protein protecting muscles until eclosion; at eclosion it becomes phosphorylated and degraded in response to Eclosion Hormone (EH). Acheron binds a novel BH3-only protein BBH1 (BAD/BNIP3 homology 1); BBH1 accumulates when muscles commit to die and is presumably liberated upon Acheron degradation, correlated with cytochrome c release and cell death. RNAi in Drosophila confirmed loss of Acheron causes precocious muscle death.\",\n      \"method\": \"Co-IP (Acheron–BBH1), phosphorylation assay (EH-stimulated), RNAi in Drosophila, cytochrome c release assay\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identifying novel binding partner BBH1, RNAi epistasis in Drosophila, multiple model organisms, single lab\",\n      \"pmids\": [\"32850788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"De novo solution NMR structure of the La domain of human LARP6 in complex with 5'SL RNA reveals a non-canonical binding interface integrating electrostatic and hydrophobic contacts with shape complementarity. Chemical shift perturbation, solvent paramagnetic relaxation enhancement, intermolecular NOEs, and targeted mutagenesis converge on this interface. The La domain alone discriminates 5'SL from homopolymeric or purely helical hairpin RNAs with low-nanomolar affinity, overturning the view that the RRM is required for recognition.\",\n      \"method\": \"Solution NMR structure determination, chemical shift perturbation, paramagnetic relaxation enhancement, intermolecular NOEs, mutagenesis, RNA binding affinity measurements\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with multiple orthogonal NMR methods plus mutagenesis validation, single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.22.652967\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The La domain of LARP6 is stabilized >50-fold when in complex with its cognate 5'SL RNA compared to the unbound (aggregation-prone) state. C-terminal truncations greatly impair protein stability while N-terminal truncations have little effect on aggregation or RNA binding.\",\n      \"method\": \"Recombinant protein expression, limited proteolysis, stability assays, RNA binding assays\",\n      \"journal\": \"ACS omega\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro biochemical characterization with multiple construct variants, single lab, published peer-reviewed\",\n      \"pmids\": [\"40191362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LARP6 regulates alternative splicing of >1000 events in MDA-MB-231 TNBC cells and tends to bind the CGACGAG motif. iRIP-seq identified 16 genes where LARP6 directly binds and regulates alternative splicing, with enrichment in DNA repair and cell cycle pathways.\",\n      \"method\": \"RNA-seq, iRIP-seq, RT-qPCR, RIP-qPCR\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — iRIP-seq with RT-qPCR validation, single lab, single method class\",\n      \"pmids\": [\"40050364\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LARP6 is an RNA-binding protein that uses its La-module (La domain + RRM1) and flanking intrinsically disordered regions to bind with low-nanomolar affinity and sequence specificity to a conserved 5' stem-loop (5'SL) in the 5'UTR of type I and III collagen mRNAs; the La domain RNK motif mediates initial 5'SL recognition while the RRM stabilizes the complex and contacts the SEC61 translocon to direct collagen mRNAs to ER membrane for coordinated translation; LARP6 activity is regulated by hierarchical phosphorylation (Akt phosphorylates S451; mTORC1 phosphorylates S348/S409, which promotes interaction with accessory protein STRAP for coordinated collagen mRNA translation and LARP6 recycling from the ER); LARP6 also binds interacting partners including FKBP3 and DNAAF6, acts upstream of MyoD in myogenesis, and broadly regulates the translation and alternative splicing of hundreds of mRNAs beyond collagen, including through binding ZNF267 mRNA to modulate sphingomyelin metabolism in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LARP6 is a sequence-specific RNA-binding protein that licenses the coordinated translation of fibrillar collagen mRNAs and, more broadly, sculpts the translation and splicing of hundreds of transcripts [#0, #11]. It recognizes a conserved 5' stem-loop (5'SL) in the 5'UTR of type I and III collagen mRNAs (COL1A1, COL1A2, COL3A1) with low-nanomolar affinity through a bipartite La-module; the La domain is necessary and sufficient for 5'SL recognition via a three-residue RNK motif in a flexible loop, while the RRM stabilizes the complex, with interdomain dynamics and an N-terminal intrinsically disordered region restricting conformational flexibility to narrow binding selectivity [#0, #1, #7, #12, #17]. Through a SEC61-contacting loop in its RRM, LARP6 directs collagen mRNAs to the ER membrane, where together with nonmuscle myosin filaments it partitions them for focal, coordinated translation; disrupting this targeting causes hypermodification, poor secretion, and cytosolic accumulation of collagen [#2, #3]. LARP6 activity is governed by hierarchical phosphorylation: Akt phosphorylates S451 as a prerequisite for further modification, and mTORC1 phosphorylates S348/S409 to promote interaction with the accessory protein STRAP and release LARP6 from the ER, with phospho-deficient mutants acting dominant-negatively on collagen biosynthesis [#5, #6]. Additional partners FKBP3, the ER-anchored CRTH2 (which routes collagen mRNA to degradation), and DNAAF6 (which co-condenses with LARP6 to support α-tubulin expression during ciliogenesis) modulate or extend these activities [#4, #8, #10]. Beyond collagen, LARP6 binds ZNF267 mRNA to perturb SGMS2-dependent sphingomyelin metabolism and autophagy in colorectal cancer, regulates >1000 alternative splicing events enriched in DNA repair and cell cycle genes, and its IDR-dependent RNA selectivity drives cancer cell viability and invasion [#9, #12, #19]. In development, LARP6 (Acheron) acts upstream of MyoD and integrin α7β1 during myogenesis and functions as a muscle survival factor in insects [#13, #14, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established LARP6 as a sequence-specific regulator of collagen biosynthesis, answering whether a dedicated factor controls type I collagen mRNA translation.\",\n      \"evidence\": \"RNA binding/Kd measurement, gel shift, siRNA knockdown, polysome profiling and collagen-GFP reporter in cells\",\n      \"pmids\": [\"19917293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of bipartite binding undefined\", \"Mechanism coupling binding to focal ER synthesis not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Independently identified LARP6 (Acheron) as a developmental regulator acting upstream of MyoD and integrin α7β1 in myogenesis, broadening its biological scope beyond collagen.\",\n      \"evidence\": \"C2C12 differentiation, dominant-negative/antisense, zebrafish morpholino, integrin expression and adhesion/migration assays\",\n      \"pmids\": [\"19481601\", \"19889961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between LARP6 RNA binding and MyoD regulation unknown\", \"Direct target mRNAs in myogenesis not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed nuclear-localized Acheron/LARP6 promotes proliferation and invasion in breast cancer, implicating it in tumorigenesis.\",\n      \"evidence\": \"NLS/NES deletion mutants, proliferation/invasion assays, xenografts, MMP-9/VEGF Western blot\",\n      \"pmids\": [\"21387291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear molecular targets not defined\", \"Relationship to cytoplasmic collagen-regulatory function unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified FKBP3 as a LARP6 partner required for collagen polypeptide translation, adding an accessory factor to the collagen translation machinery.\",\n      \"evidence\": \"Co-IP, FK506 perturbation, in vitro collagen synthesis assay\",\n      \"pmids\": [\"23755290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of FKBP3 contribution to translation unresolved\", \"Single lab, no reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the structural and sequence determinants of 5'SL recognition and linked LARP6 to the SEC61 translocon, explaining how it couples mRNA binding to ER-targeted collagen synthesis.\",\n      \"evidence\": \"X-ray crystallography/NMR of La-module, mutagenesis, gel shift, Co-IP with SEC61, dominant-negative overexpression, ER fractionation with nonmuscle myosin perturbation\",\n      \"pmids\": [\"25488812\", \"25692237\", \"25271881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the La-domain–5'SL complex still missing\", \"How myosin filaments physically partition mRNAs unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed hierarchical Akt and mTORC1 phosphorylation as the regulatory switch controlling LARP6 function and ER recycling via STRAP.\",\n      \"evidence\": \"MS phosphosite mapping, kinase inhibition, site-directed mutagenesis with dominant-negative readouts, Co-IP with STRAP, ER fractionation\",\n      \"pmids\": [\"26932461\", \"28112218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order and stoichiometry of all 8 phosphosites incomplete\", \"STRAP's mechanistic role in coordinated translation undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Pinpointed the La-domain RNK motif as the necessary and sufficient determinant of 5'SL specificity and identified CRTH2 as an upstream negative regulator of collagen mRNA stability.\",\n      \"evidence\": \"Mutagenesis, UV crosslinking, domain deletion; reciprocal Co-IP, caveolin-1 KO, genetic epistasis with rescue\",\n      \"pmids\": [\"34896113\", \"34223653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of RNK–RNA contact not yet atomic\", \"How CRTH2 routes bound mRNA to degradation unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended LARP6 targets beyond collagen to ZNF267 mRNA, linking it to sphingomyelin metabolism and autophagy in colorectal cancer.\",\n      \"evidence\": \"RIP-seq/RIP-qPCR, overexpression/knockdown, Western blot, autophagy assays\",\n      \"pmids\": [\"36691044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect regulation of SGMS2 not separated\", \"Whether 5'SL-like elements mediate ZNF267 binding unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that LARP6–DNAAF6 condensates drive α-tubulin mRNA expression for ciliogenesis, defining a distinct condensate-based function.\",\n      \"evidence\": \"Co-IP, live colocalization imaging, Xenopus morphant/rescue with binding-deficient DNAAF6 mutant\",\n      \"pmids\": [\"38762183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether condensate formation is required for translation control untested\", \"Conservation in mammalian ciliogenesis not shown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Genome-wide profiling redefined LARP6 as a broad RNA regulator binding >300 mature mRNAs and over a thousand splicing events, with an IDR that narrows its RNA selectivity to support cancer phenotypes.\",\n      \"evidence\": \"eCLIP, ribosome profiling, IP-MS, iCLIP, iRIP-seq, mutagenesis, cancer cell viability/invasion and splicing assays\",\n      \"pmids\": [\"41746718\", \"41714637\", \"40050364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of most bound transcripts not validated\", \"Coupling between IDR-restricted binding and specific splicing/translation outcomes incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Solution structure and stability studies of the La domain–5'SL complex showed the La domain alone discriminates 5'SL with low-nanomolar affinity and is stabilized >50-fold upon binding.\",\n      \"evidence\": \"Solution NMR structure (preprint), CSP/PRE/NOEs, mutagenesis; limited proteolysis and stability assays with truncations\",\n      \"pmids\": [\"bio_10.1101_2025.05.22.652967\", \"40191362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NMR structure awaits peer review\", \"Role of full-length protein and RRM in vivo selectivity vs isolated La domain not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LARP6's discrete activities—ER-coupled collagen translation, condensate-based ciliogenesis, nuclear pro-tumorigenic signaling, and genome-wide splicing—are integrated under a single regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking phosphorylation state to target choice\", \"Functional significance of most non-collagen targets unvalidated\", \"Mammalian relevance of model-organism developmental roles untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 7, 11, 12, 17, 19]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 3, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 3, 6, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 3, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [11, 19]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 3, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 14, 10]}\n    ],\n    \"complexes\": [\"dynein axonemal particle (LARP6–DNAAF6 condensate)\"],\n    \"partners\": [\"SEC61\", \"STRAP\", \"FKBP3\", \"CRTH2\", \"DNAAF6\", \"BBH1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}