{"gene":"ANXA11","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2024,"finding":"Cryo-EM structures of filaments from FTLD-TDP type C brains revealed that ANXA11 and TDP-43 co-assemble into heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284-N345 and ANXA11 residues L39-Y74 from their respective low-complexity domains, with an extensive hydrophobic interface at the filament centre. The majority of ANXA11 in these filaments exists as an ~22 kDa N-terminal fragment lacking the annexin core domain.","method":"Cryo-electron microscopy of patient brain-derived filaments, immunoblotting, immunohistochemistry","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution cryo-EM structure from patient brain material with multiple orthogonal validations","pmids":["39260416"],"is_preprint":false},{"year":2025,"finding":"ANXA11 tethers RNP granule condensates to lysosomal membranes to enable their co-trafficking. The low-complexity N-terminus of ANXA11 drives protein phase transitions that induce coupled phase state changes in the lipids of the underlying lysosomal membrane. ALG2 and CALC were identified as interacting proteins that potently regulate ANXA11-based phase coupling and influence the nanomechanical properties of the ANXA11-lysosome ensemble and its capacity to engage RNP granules.","method":"Live-cell imaging, Co-IP, biophysical assays of membrane nanomechanics, protein phase separation assays, identification of interacting proteins","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biophysical and cell biological methods, peer-reviewed","pmids":["40118863"],"is_preprint":false},{"year":2020,"finding":"ANXA11 regulates intracellular Ca2+ homeostasis and stress granule dynamics. ALS-associated N-terminal low-complexity domain variants (p.G38R, p.D40G) enhanced aggregation propensity and underwent abnormal phase separation; C-terminal ANX domain variants (p.H390P, p.R456H) altered Ca2+ responses. All variants caused alterations in intracellular Ca2+ homeostasis and stress granule disassembly. Ca2+-dependent interaction and co-aggregation between ANXA11 and ALS-causative RNA-binding proteins FUS and hnRNPA1 were observed, and ALS-linked variants caused cytoplasmic sequestration of endogenous FUS and triggered neuronal apoptosis.","method":"Exome sequencing, calcium imaging, stress granule dynamics assays, phase separation assays, Co-IP, immunofluorescence in motor neuron cells and patient brain","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays in relevant cell models with patient-derived material","pmids":["33087501"],"is_preprint":false},{"year":2025,"finding":"Ca2+ acts as a master regulator of ANXA11 physiological function by modulating conformational states. In the absence of Ca2+, the N-terminal and C-terminal domains interact with each other (closed state); in the presence of Ca2+, this self-interaction is disrupted (open state), allowing both domains to freely interact with RNA and liposomes simultaneously. The ALS-associated p.D40G mutation in the N-terminal domain destabilizes interdomain interactions and bypasses Ca2+ regulation, leading to aberrant aggregation.","method":"Recombinant protein studies, liposome binding assays, RNA binding assays, multidisciplinary biophysical approaches, mutagenesis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis, but preprint only","pmids":["bio_10.1101_2025.10.27.684738"],"is_preprint":true},{"year":2025,"finding":"In a knock-in mouse model carrying the ALS-associated ANXA11 p.P36R mutation, mutant ANXA11 co-aggregated with TDP-43 and SQSTM1/p62-positive inclusions in spinal cord motor neurons, cortical neurons, and muscle cells from 2 months of age. Autophagic flux was intact at 2 months but impaired by 9 months (decreased Beclin-1 and LC3BII/I, increased SQSTM1/p62, mTORC1 hyperactivation), with motor neuron loss and neuroinflammation by 9 months, demonstrating a gain-of-function mechanism involving autophagy impairment.","method":"Knock-in mouse model, electron microscopy, immunofluorescence, western blot, autophagic flux assays","journal":"Acta neuropathologica communications","confidence":"High","confidence_rationale":"Tier 2 — in vivo knock-in model with multiple orthogonal readouts across time points","pmids":["39755715"],"is_preprint":false},{"year":2024,"finding":"ANXA11 P93S variant led to decreased lysosome colocalization, decreased neuritic RNA, and decreased nuclear TDP-43 with cryptic exon expression in iPSC-derived neurons, establishing that ANXA11 mutations alter lysosomal-RNA granule co-trafficking and TDP-43 biology.","method":"iPSC-derived neurons, immunofluorescence, HCR FISH for cryptic exons, multiomic profiling","journal":"Alzheimer's & dementia","confidence":"Medium","confidence_rationale":"Tier 2 — iPSC-derived neurons with multiple orthogonal readouts, single lab","pmids":["38923692"],"is_preprint":false},{"year":2023,"finding":"Recombinant ANXA11 p.Asp40Ile showed abnormal phase separation and was more aggregation-prone than ALS-associated ANXA11 p.Asp40Gly in vitro. Patient fibroblasts revealed defects in stress granule dynamics and clearance, and muscle histopathology showed ANXA11 protein aggregates, demonstrating that Asp40 variants share a common pathophysiology of enhanced aggregation propensity and stress granule dysfunction.","method":"Recombinant protein phase separation assay, patient fibroblast stress granule assays, muscle biopsy histopathology, super-resolution imaging","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro reconstitution plus patient-derived cell and tissue studies, single lab","pmids":["36651622"],"is_preprint":false},{"year":2022,"finding":"Patient fibroblasts carrying ALS-FTD-linked ANXA11 variants p.P36R and p.D40G exhibited impaired intracellular calcium homeostasis, defective stress granule disassembly, and impaired protein translation, functionally validating these variants' pathogenicity.","method":"Patient fibroblast calcium imaging, stress granule dynamics assays, protein translation assays","journal":"Brain communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays in patient-derived cells, single lab","pmids":["36458208"],"is_preprint":false},{"year":2024,"finding":"ANXA11 functions as a non-canonical RNA-binding protein that binds miR-148a-3p in a sequence-specific manner (demonstrated by RNA pull-down, mass spectrometry, and EMSA). ANXA11 retains miR-148a-3p intracellularly, and its reduction upon cisplatin stimulation promotes miR-148a-3p efflux through small extracellular vesicles, mediating cisplatin resistance.","method":"RNA pull-down, mass spectrometry, EMSA, immunostaining, microRNA FISH, in vivo xenograft experiments","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — direct RNA-binding demonstrated by multiple biochemical methods including EMSA, single lab","pmids":["39259536"],"is_preprint":false},{"year":2016,"finding":"ANXA11 knockdown in hepatocarcinoma Hca-P cells promoted migration, invasion, lymph node metastasis, and 5-FU chemoresistance via modulation of c-Jun phosphorylation (increased c-Jun pSer73, decreased c-Jun pSer243), placing ANXA11 upstream of c-Jun in a tumor suppressor pathway.","method":"Stable shRNA knockdown, in vitro migration/invasion assays, in vivo tumor growth and lymph node metastasis assays, western blot for c-Jun phosphorylation states","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro loss-of-function with defined phosphorylation-based mechanistic readout, single lab","pmids":["26908448"],"is_preprint":false},{"year":2018,"finding":"siRNA silencing of ANXA11 in gastric cancer cells inhibited cell proliferation, colony formation, migration, and invasion through the AKT/GSK-3β pathway, placing ANXA11 as an upstream regulator of AKT/GSK-3β signaling in gastric cancer.","method":"siRNA knockdown, proliferation/migration/invasion assays, western blot for AKT/GSK-3β pathway","journal":"Medical science monitor","confidence":"Low","confidence_rationale":"Tier 3 — single lab, loss-of-function with signaling pathway readout but limited mechanistic depth","pmids":["29306955"],"is_preprint":false},{"year":2024,"finding":"ANXA11 and CHMP2B act sequentially in plasma membrane repair: Annexins (including ANXA11) are recruited immediately to sites of membrane damage to seal membranes, while ESCRT-III assembles only after membrane sealing to shed damaged membrane fragments. ALS/FTD-associated mutations in ANXA11 compromise this repair process.","method":"Live-cell imaging of membrane damage recruitment kinetics, loss-of-function with ALS/FTD-associated mutations, membrane integrity assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — temporal recruitment assays with functional mutagenesis, but preprint only","pmids":["bio_10.1101_2024.11.19.624330"],"is_preprint":true},{"year":2025,"finding":"β-Hydroxybutyrylation (kbhb) of ANXA11 was detected by Co-IP in high-glucose conditions, and ANXA11 was found to bind Cep55. ANXA11 overexpression increased γ-Tubulin and PLK4 expression and decreased mitochondrial membrane potential and ATP levels, implicating ANXA11 in centriole duplication and mitochondrial dysfunction in diabetic cardiomyopathy.","method":"Co-IP for kbhb modification and Cep55 binding, western blot, immunofluorescence, mitochondrial membrane potential and ATP assays, in vivo diabetic cardiomyopathy model","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 — single lab, Co-IP-based PTM identification with overexpression phenotype, limited mechanistic resolution","pmids":["40865591"],"is_preprint":false},{"year":1998,"finding":"Fluorescence in situ hybridization localized human ANX11 (ANXA11) to chromosomal region 10q22.3-q23.1, establishing its genomic position and phylogenetic analysis suggested annexin A11 as the putative primary progenitor of up to nine paralogous human annexins.","method":"Fluorescence in situ hybridization (FISH), phylogenetic analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct cytogenetic localization by FISH","pmids":["9503022"],"is_preprint":false}],"current_model":"ANXA11 is a Ca2+-dependent phospholipid-binding protein that functions as a molecular tether linking RNP granules to lysosomes for co-trafficking via its low-complexity N-terminus (which binds RNA and drives phase separation) and its C-terminal annexin core (which associates with lysosomal membranes); Ca2+ acts as a master conformational switch between a closed auto-inhibited state and an open active state permitting simultaneous RNA and membrane binding. ALS/FTD-associated mutations in the N-terminal low-complexity domain (e.g., G38R, D40G, P36R) enhance aggregation propensity, bypass Ca2+ regulation, disrupt stress granule disassembly and Ca2+ homeostasis, cause TDP-43 mislocalization, and impair autophagy, while in FTLD-TDP type C, ANXA11 (as an ~22 kDa N-terminal fragment) co-assembles with TDP-43 into unprecedented heteromeric amyloid filaments via an extensive hydrophobic interface between their respective low-complexity domains."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing the genomic position and evolutionary origin of ANXA11 provided the foundation for subsequent functional studies by mapping the gene to 10q22.3-q23.1 and identifying it as a candidate progenitor of multiple human annexins.","evidence":"Fluorescence in situ hybridization and phylogenetic analysis","pmids":["9503022"],"confidence":"Medium","gaps":["No functional data at this stage","Evolutionary relationship to other annexins based on sequence alone"]},{"year":2016,"claim":"Loss-of-function studies first placed ANXA11 in cellular signaling pathways by showing that its depletion promoted migration, invasion, and chemoresistance through altered c-Jun phosphorylation, suggesting a tumor-suppressive role.","evidence":"shRNA knockdown in hepatocarcinoma cells with in vivo metastasis assays and c-Jun phosphorylation readouts","pmids":["26908448"],"confidence":"Medium","gaps":["Direct biochemical link between ANXA11 and c-Jun kinase/phosphatase not established","Single cancer cell line","Not replicated independently"]},{"year":2020,"claim":"A key advance was demonstrating that ALS-associated mutations in the N-terminal low-complexity domain enhanced aggregation and aberrant phase separation, while C-terminal variants altered Ca²⁺ responses, unifying calcium homeostasis, stress granule dynamics, and neurodegeneration under a single ANXA11 mechanism.","evidence":"Exome sequencing, calcium imaging, phase separation and stress granule assays, Co-IP in motor neuron cells and patient brain tissue","pmids":["33087501"],"confidence":"High","gaps":["Structural basis of Ca²⁺-dependent conformational change unknown","Whether stress granule defects are cause or consequence of neurodegeneration unclear"]},{"year":2022,"claim":"Patient-derived fibroblasts carrying P36R and D40G mutations validated that impaired calcium homeostasis, defective stress granule disassembly, and impaired protein translation are cell-autonomous consequences of these variants.","evidence":"Patient fibroblast calcium imaging, stress granule dynamics, and translation assays","pmids":["36458208"],"confidence":"Medium","gaps":["Fibroblasts rather than neurons used","Translation impairment mechanism not defined at molecular level"]},{"year":2023,"claim":"Biochemical reconstitution showed that the D40I variant is even more aggregation-prone than D40G, establishing a graded spectrum of phase separation defects at the Asp40 position and confirming stress granule dysfunction in patient tissue.","evidence":"Recombinant protein phase separation assays, patient fibroblast stress granule assays, muscle biopsy histopathology","pmids":["36651622"],"confidence":"Medium","gaps":["Quantitative relationship between aggregation propensity and disease severity not established","Single lab study"]},{"year":2024,"claim":"The landmark discovery that ANXA11 and TDP-43 co-assemble into heteromeric amyloid filaments in FTLD-TDP type C brains, with an extensive hydrophobic interface between their low-complexity domains, fundamentally redefined the pathological role of ANXA11 from a bystander to a structural co-component of disease-defining inclusions.","evidence":"Cryo-EM of patient brain-derived filaments at atomic resolution, immunoblotting, immunohistochemistry","pmids":["39260416"],"confidence":"High","gaps":["Whether heteromeric filaments form in ALS as well as FTLD-TDP type C is unknown","Mechanism of N-terminal cleavage generating the ~22 kDa fragment is unidentified","Whether co-assembly is required for toxicity or is an end-stage phenomenon unclear"]},{"year":2024,"claim":"ANXA11 was established as a non-canonical RNA-binding protein that binds miR-148a-3p in a sequence-specific manner, with its intracellular retention of miRNA modulating extracellular vesicle-mediated chemoresistance signaling.","evidence":"RNA pull-down, mass spectrometry, EMSA, microRNA FISH, in vivo xenograft","pmids":["39259536"],"confidence":"Medium","gaps":["RNA-binding specificity determinants in ANXA11 not mapped","Generality of miRNA regulation beyond miR-148a-3p unknown"]},{"year":2024,"claim":"iPSC-derived neuron studies with the P93S variant demonstrated that ANXA11 mutations decrease lysosome–RNA granule co-localization, reduce neuritic RNA, and cause nuclear TDP-43 loss with cryptic exon expression, directly linking the tethering function to TDP-43 nuclear biology.","evidence":"iPSC-derived neurons, immunofluorescence, HCR FISH for cryptic exons","pmids":["38923692"],"confidence":"Medium","gaps":["Causal chain from lysosome–RNA granule uncoupling to TDP-43 nuclear loss not mechanistically resolved","Single mutation studied"]},{"year":2025,"claim":"The P36R knock-in mouse model provided the first in vivo demonstration that mutant ANXA11 causes progressive TDP-43 and p62-positive co-aggregation, autophagy impairment via mTORC1 hyperactivation, motor neuron loss, and neuroinflammation, establishing a gain-of-function disease mechanism.","evidence":"Knock-in mouse model with longitudinal analysis at 2 and 9 months, electron microscopy, autophagic flux assays","pmids":["39755715"],"confidence":"High","gaps":["How ANXA11 aggregates impair autophagy and activate mTORC1 at the molecular level is undefined","Whether motor phenotype fully recapitulates ALS not assessed"]},{"year":2025,"claim":"The physiological tethering function was mechanistically elaborated: ANXA11's N-terminal phase separation induces coupled phase state changes in lysosomal membrane lipids, and the interacting proteins ALG2 and CALC regulate this phase coupling and the nanomechanical properties of the ANXA11–lysosome ensemble.","evidence":"Live-cell imaging, Co-IP, biophysical membrane nanomechanics assays, phase separation assays","pmids":["40118863"],"confidence":"High","gaps":["Structural details of ALG2/CALC regulation of ANXA11 phase coupling not resolved","How membrane lipid phase changes influence RNP granule engagement is not fully defined"]},{"year":null,"claim":"Key unresolved questions include the structural basis of full-length ANXA11's Ca²⁺-dependent conformational switch at atomic resolution, the protease responsible for generating the ~22 kDa N-terminal fragment found in FTLD filaments, and whether ANXA11–TDP-43 heteromeric amyloid formation is a cause or consequence of neurodegeneration.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of full-length ANXA11 in either conformational state","Identity of the protease generating the pathological N-terminal fragment is unknown","Causal versus consequential role of heteromeric amyloid filaments in disease not tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,2]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,4]}],"complexes":["ANXA11–TDP-43 heteromeric amyloid filament"],"partners":["TDP43","ALG2","FUS","HNRNPA1","CEP55","CHMP2B"],"other_free_text":[]},"mechanistic_narrative":"ANXA11 is a Ca²⁺-dependent phospholipid-binding protein that tethers ribonucleoprotein (RNP) granules to lysosomal membranes for co-trafficking, couples RNA binding and membrane association through a conformational switch between a closed auto-inhibited state and an open Ca²⁺-activated state, and participates in plasma membrane repair [PMID:40118863, PMID:33087501]. The low-complexity N-terminal domain drives liquid–liquid phase separation, binds RNA (including specific microRNAs such as miR-148a-3p), and mediates interactions with stress granule components FUS and hnRNPA1, while the C-terminal annexin core domain confers Ca²⁺-regulated liposome and membrane binding [PMID:33087501, PMID:39259536, PMID:40118863]. ALS- and FTD-associated mutations in the N-terminal domain (e.g., G38R, D40G, P36R) enhance aggregation propensity, bypass Ca²⁺ regulation, impair stress granule disassembly and calcium homeostasis, cause TDP-43 mislocalization and co-aggregation, and progressively disrupt autophagy in vivo [PMID:33087501, PMID:39755715, PMID:38923692]. In FTLD-TDP type C, the ANXA11 N-terminal low-complexity domain co-assembles with TDP-43 into heteromeric amyloid filaments resolved at atomic resolution by cryo-EM [PMID:39260416]."},"prefetch_data":{"uniprot":{"accession":"P50995","full_name":"Annexin A11","aliases":["56 kDa autoantigen","Annexin XI","Annexin-11","Calcyclin-associated annexin 50","CAP-50"],"length_aa":505,"mass_kda":54.4,"function":"Binds specifically to calcyclin in a calcium-dependent manner (By similarity). Required for midbody formation and completion of the terminal phase of cytokinesis","subcellular_location":"Cytoplasm; Melanosome; Nucleus envelope; Nucleus, nucleoplasm; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/P50995/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANXA11","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000122359","cell_line_id":"CID001094","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"nuclear_punctae","grade":2}],"interactors":[{"gene":"PRDX3","stoichiometry":10.0},{"gene":"OAT","stoichiometry":4.0},{"gene":"CALD1","stoichiometry":0.2},{"gene":"HSPBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001094","total_profiled":1310},"omim":[{"mim_id":"619733","title":"INCLUSION BODY MYOPATHY AND BRAIN WHITE MATTER ABNORMALITIES; IBMWMA","url":"https://www.omim.org/entry/619733"},{"mim_id":"617839","title":"AMYOTROPHIC LATERAL SCLEROSIS 23; ALS23","url":"https://www.omim.org/entry/617839"},{"mim_id":"612388","title":"SARCOIDOSIS, SUSCEPTIBILITY TO, 3; SS3","url":"https://www.omim.org/entry/612388"},{"mim_id":"602572","title":"ANNEXIN A11; ANXA11","url":"https://www.omim.org/entry/602572"},{"mim_id":"602396","title":"ANNEXIN A8; ANXA8","url":"https://www.omim.org/entry/602396"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANXA11"},"hgnc":{"alias_symbol":[],"prev_symbol":["ANX11"]},"alphafold":{"accession":"P50995","domains":[{"cath_id":"1.10.220.10","chopping":"201-258","consensus_level":"high","plddt":97.1429,"start":201,"end":258},{"cath_id":"1.10.220.10","chopping":"346-415_422-428","consensus_level":"medium","plddt":95.9805,"start":346,"end":428},{"cath_id":"1.10.220.10","chopping":"431-505","consensus_level":"medium","plddt":96.9977,"start":431,"end":505}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P50995","model_url":"https://alphafold.ebi.ac.uk/files/AF-P50995-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P50995-F1-predicted_aligned_error_v6.png","plddt_mean":75.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANXA11","jax_strain_url":"https://www.jax.org/strain/search?query=ANXA11"},"sequence":{"accession":"P50995","fasta_url":"https://rest.uniprot.org/uniprotkb/P50995.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P50995/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P50995"}},"corpus_meta":[{"pmid":"19165924","id":"PMC_19165924","title":"Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19165924","citation_count":201,"is_preprint":false},{"pmid":"31088485","id":"PMC_31088485","title":"Long non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinoma.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31088485","citation_count":110,"is_preprint":false},{"pmid":"33087501","id":"PMC_33087501","title":"ANXA11 mutations in ALS cause dysregulation of calcium homeostasis and stress granule dynamics.","date":"2020","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33087501","citation_count":71,"is_preprint":false},{"pmid":"39260416","id":"PMC_39260416","title":"Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/39260416","citation_count":64,"is_preprint":false},{"pmid":"23151485","id":"PMC_23151485","title":"Association of ANXA11 genetic variation with sarcoidosis in African Americans and European Americans.","date":"2012","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/23151485","citation_count":53,"is_preprint":false},{"pmid":"29845112","id":"PMC_29845112","title":"ANXA11 mutations prevail in Chinese ALS patients with and without cognitive dementia.","date":"2018","source":"Neurology. 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the tumorigenesis, lymph node metastasis and 5-fluorouracil sensitivity of murine hepatocarcinoma Hca-P cells by targeting c-Jun.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26908448","citation_count":11,"is_preprint":false},{"pmid":"36651622","id":"PMC_36651622","title":"Common pathophysiology for ANXA11 disorders caused by aspartate 40 variants.","date":"2023","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36651622","citation_count":10,"is_preprint":false},{"pmid":"36873447","id":"PMC_36873447","title":"An atypical ALS with PSP-like symptoms caused by ANXA11 p.D40G mutation: A case report and literature review.","date":"2023","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36873447","citation_count":10,"is_preprint":false},{"pmid":"32905397","id":"PMC_32905397","title":"EIF3J-AS1 promotes glioma cell growth via up-regulating ANXA11 through sponging 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Alzheimer's Association","url":"https://pubmed.ncbi.nlm.nih.gov/40042459","citation_count":9,"is_preprint":false},{"pmid":"39755715","id":"PMC_39755715","title":"Gain-of-function ANXA11 mutation cause late-onset ALS with aberrant protein aggregation, neuroinflammation and autophagy impairment.","date":"2025","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/39755715","citation_count":9,"is_preprint":false},{"pmid":"33610019","id":"PMC_33610019","title":"Generation of six induced pluripotent stem cell lines from patients with amyotrophic lateral sclerosis with associated genetic mutations in either FUS or ANXA11.","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33610019","citation_count":5,"is_preprint":false},{"pmid":"38979278","id":"PMC_38979278","title":"Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C.","date":"2024","source":"bioRxiv : the preprint server for 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ANXA11 and TDP-43 co-assemble into heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284-N345 and ANXA11 residues L39-Y74 from their respective low-complexity domains, with an extensive hydrophobic interface at the filament centre. The majority of ANXA11 in these filaments exists as an ~22 kDa N-terminal fragment lacking the annexin core domain.\",\n      \"method\": \"Cryo-electron microscopy of patient brain-derived filaments, immunoblotting, immunohistochemistry\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution cryo-EM structure from patient brain material with multiple orthogonal validations\",\n      \"pmids\": [\"39260416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANXA11 tethers RNP granule condensates to lysosomal membranes to enable their co-trafficking. The low-complexity N-terminus of ANXA11 drives protein phase transitions that induce coupled phase state changes in the lipids of the underlying lysosomal membrane. ALG2 and CALC were identified as interacting proteins that potently regulate ANXA11-based phase coupling and influence the nanomechanical properties of the ANXA11-lysosome ensemble and its capacity to engage RNP granules.\",\n      \"method\": \"Live-cell imaging, Co-IP, biophysical assays of membrane nanomechanics, protein phase separation assays, identification of interacting proteins\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biophysical and cell biological methods, peer-reviewed\",\n      \"pmids\": [\"40118863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA11 regulates intracellular Ca2+ homeostasis and stress granule dynamics. ALS-associated N-terminal low-complexity domain variants (p.G38R, p.D40G) enhanced aggregation propensity and underwent abnormal phase separation; C-terminal ANX domain variants (p.H390P, p.R456H) altered Ca2+ responses. All variants caused alterations in intracellular Ca2+ homeostasis and stress granule disassembly. Ca2+-dependent interaction and co-aggregation between ANXA11 and ALS-causative RNA-binding proteins FUS and hnRNPA1 were observed, and ALS-linked variants caused cytoplasmic sequestration of endogenous FUS and triggered neuronal apoptosis.\",\n      \"method\": \"Exome sequencing, calcium imaging, stress granule dynamics assays, phase separation assays, Co-IP, immunofluorescence in motor neuron cells and patient brain\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays in relevant cell models with patient-derived material\",\n      \"pmids\": [\"33087501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ca2+ acts as a master regulator of ANXA11 physiological function by modulating conformational states. In the absence of Ca2+, the N-terminal and C-terminal domains interact with each other (closed state); in the presence of Ca2+, this self-interaction is disrupted (open state), allowing both domains to freely interact with RNA and liposomes simultaneously. The ALS-associated p.D40G mutation in the N-terminal domain destabilizes interdomain interactions and bypasses Ca2+ regulation, leading to aberrant aggregation.\",\n      \"method\": \"Recombinant protein studies, liposome binding assays, RNA binding assays, multidisciplinary biophysical approaches, mutagenesis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis, but preprint only\",\n      \"pmids\": [\"bio_10.1101_2025.10.27.684738\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a knock-in mouse model carrying the ALS-associated ANXA11 p.P36R mutation, mutant ANXA11 co-aggregated with TDP-43 and SQSTM1/p62-positive inclusions in spinal cord motor neurons, cortical neurons, and muscle cells from 2 months of age. Autophagic flux was intact at 2 months but impaired by 9 months (decreased Beclin-1 and LC3BII/I, increased SQSTM1/p62, mTORC1 hyperactivation), with motor neuron loss and neuroinflammation by 9 months, demonstrating a gain-of-function mechanism involving autophagy impairment.\",\n      \"method\": \"Knock-in mouse model, electron microscopy, immunofluorescence, western blot, autophagic flux assays\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knock-in model with multiple orthogonal readouts across time points\",\n      \"pmids\": [\"39755715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANXA11 P93S variant led to decreased lysosome colocalization, decreased neuritic RNA, and decreased nuclear TDP-43 with cryptic exon expression in iPSC-derived neurons, establishing that ANXA11 mutations alter lysosomal-RNA granule co-trafficking and TDP-43 biology.\",\n      \"method\": \"iPSC-derived neurons, immunofluorescence, HCR FISH for cryptic exons, multiomic profiling\",\n      \"journal\": \"Alzheimer's & dementia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — iPSC-derived neurons with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"38923692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Recombinant ANXA11 p.Asp40Ile showed abnormal phase separation and was more aggregation-prone than ALS-associated ANXA11 p.Asp40Gly in vitro. Patient fibroblasts revealed defects in stress granule dynamics and clearance, and muscle histopathology showed ANXA11 protein aggregates, demonstrating that Asp40 variants share a common pathophysiology of enhanced aggregation propensity and stress granule dysfunction.\",\n      \"method\": \"Recombinant protein phase separation assay, patient fibroblast stress granule assays, muscle biopsy histopathology, super-resolution imaging\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution plus patient-derived cell and tissue studies, single lab\",\n      \"pmids\": [\"36651622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Patient fibroblasts carrying ALS-FTD-linked ANXA11 variants p.P36R and p.D40G exhibited impaired intracellular calcium homeostasis, defective stress granule disassembly, and impaired protein translation, functionally validating these variants' pathogenicity.\",\n      \"method\": \"Patient fibroblast calcium imaging, stress granule dynamics assays, protein translation assays\",\n      \"journal\": \"Brain communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays in patient-derived cells, single lab\",\n      \"pmids\": [\"36458208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANXA11 functions as a non-canonical RNA-binding protein that binds miR-148a-3p in a sequence-specific manner (demonstrated by RNA pull-down, mass spectrometry, and EMSA). ANXA11 retains miR-148a-3p intracellularly, and its reduction upon cisplatin stimulation promotes miR-148a-3p efflux through small extracellular vesicles, mediating cisplatin resistance.\",\n      \"method\": \"RNA pull-down, mass spectrometry, EMSA, immunostaining, microRNA FISH, in vivo xenograft experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA-binding demonstrated by multiple biochemical methods including EMSA, single lab\",\n      \"pmids\": [\"39259536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ANXA11 knockdown in hepatocarcinoma Hca-P cells promoted migration, invasion, lymph node metastasis, and 5-FU chemoresistance via modulation of c-Jun phosphorylation (increased c-Jun pSer73, decreased c-Jun pSer243), placing ANXA11 upstream of c-Jun in a tumor suppressor pathway.\",\n      \"method\": \"Stable shRNA knockdown, in vitro migration/invasion assays, in vivo tumor growth and lymph node metastasis assays, western blot for c-Jun phosphorylation states\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro loss-of-function with defined phosphorylation-based mechanistic readout, single lab\",\n      \"pmids\": [\"26908448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"siRNA silencing of ANXA11 in gastric cancer cells inhibited cell proliferation, colony formation, migration, and invasion through the AKT/GSK-3β pathway, placing ANXA11 as an upstream regulator of AKT/GSK-3β signaling in gastric cancer.\",\n      \"method\": \"siRNA knockdown, proliferation/migration/invasion assays, western blot for AKT/GSK-3β pathway\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, loss-of-function with signaling pathway readout but limited mechanistic depth\",\n      \"pmids\": [\"29306955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANXA11 and CHMP2B act sequentially in plasma membrane repair: Annexins (including ANXA11) are recruited immediately to sites of membrane damage to seal membranes, while ESCRT-III assembles only after membrane sealing to shed damaged membrane fragments. ALS/FTD-associated mutations in ANXA11 compromise this repair process.\",\n      \"method\": \"Live-cell imaging of membrane damage recruitment kinetics, loss-of-function with ALS/FTD-associated mutations, membrane integrity assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — temporal recruitment assays with functional mutagenesis, but preprint only\",\n      \"pmids\": [\"bio_10.1101_2024.11.19.624330\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"β-Hydroxybutyrylation (kbhb) of ANXA11 was detected by Co-IP in high-glucose conditions, and ANXA11 was found to bind Cep55. ANXA11 overexpression increased γ-Tubulin and PLK4 expression and decreased mitochondrial membrane potential and ATP levels, implicating ANXA11 in centriole duplication and mitochondrial dysfunction in diabetic cardiomyopathy.\",\n      \"method\": \"Co-IP for kbhb modification and Cep55 binding, western blot, immunofluorescence, mitochondrial membrane potential and ATP assays, in vivo diabetic cardiomyopathy model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP-based PTM identification with overexpression phenotype, limited mechanistic resolution\",\n      \"pmids\": [\"40865591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Fluorescence in situ hybridization localized human ANX11 (ANXA11) to chromosomal region 10q22.3-q23.1, establishing its genomic position and phylogenetic analysis suggested annexin A11 as the putative primary progenitor of up to nine paralogous human annexins.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH), phylogenetic analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cytogenetic localization by FISH\",\n      \"pmids\": [\"9503022\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANXA11 is a Ca2+-dependent phospholipid-binding protein that functions as a molecular tether linking RNP granules to lysosomes for co-trafficking via its low-complexity N-terminus (which binds RNA and drives phase separation) and its C-terminal annexin core (which associates with lysosomal membranes); Ca2+ acts as a master conformational switch between a closed auto-inhibited state and an open active state permitting simultaneous RNA and membrane binding. ALS/FTD-associated mutations in the N-terminal low-complexity domain (e.g., G38R, D40G, P36R) enhance aggregation propensity, bypass Ca2+ regulation, disrupt stress granule disassembly and Ca2+ homeostasis, cause TDP-43 mislocalization, and impair autophagy, while in FTLD-TDP type C, ANXA11 (as an ~22 kDa N-terminal fragment) co-assembles with TDP-43 into unprecedented heteromeric amyloid filaments via an extensive hydrophobic interface between their respective low-complexity domains.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ANXA11 is a Ca²⁺-dependent phospholipid-binding protein that tethers ribonucleoprotein (RNP) granules to lysosomal membranes for co-trafficking, couples RNA binding and membrane association through a conformational switch between a closed auto-inhibited state and an open Ca²⁺-activated state, and participates in plasma membrane repair [PMID:40118863, PMID:33087501]. The low-complexity N-terminal domain drives liquid–liquid phase separation, binds RNA (including specific microRNAs such as miR-148a-3p), and mediates interactions with stress granule components FUS and hnRNPA1, while the C-terminal annexin core domain confers Ca²⁺-regulated liposome and membrane binding [PMID:33087501, PMID:39259536, PMID:40118863]. ALS- and FTD-associated mutations in the N-terminal domain (e.g., G38R, D40G, P36R) enhance aggregation propensity, bypass Ca²⁺ regulation, impair stress granule disassembly and calcium homeostasis, cause TDP-43 mislocalization and co-aggregation, and progressively disrupt autophagy in vivo [PMID:33087501, PMID:39755715, PMID:38923692]. In FTLD-TDP type C, the ANXA11 N-terminal low-complexity domain co-assembles with TDP-43 into heteromeric amyloid filaments resolved at atomic resolution by cryo-EM [PMID:39260416].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing the genomic position and evolutionary origin of ANXA11 provided the foundation for subsequent functional studies by mapping the gene to 10q22.3-q23.1 and identifying it as a candidate progenitor of multiple human annexins.\",\n      \"evidence\": \"Fluorescence in situ hybridization and phylogenetic analysis\",\n      \"pmids\": [\"9503022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional data at this stage\", \"Evolutionary relationship to other annexins based on sequence alone\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Loss-of-function studies first placed ANXA11 in cellular signaling pathways by showing that its depletion promoted migration, invasion, and chemoresistance through altered c-Jun phosphorylation, suggesting a tumor-suppressive role.\",\n      \"evidence\": \"shRNA knockdown in hepatocarcinoma cells with in vivo metastasis assays and c-Jun phosphorylation readouts\",\n      \"pmids\": [\"26908448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between ANXA11 and c-Jun kinase/phosphatase not established\", \"Single cancer cell line\", \"Not replicated independently\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A key advance was demonstrating that ALS-associated mutations in the N-terminal low-complexity domain enhanced aggregation and aberrant phase separation, while C-terminal variants altered Ca²⁺ responses, unifying calcium homeostasis, stress granule dynamics, and neurodegeneration under a single ANXA11 mechanism.\",\n      \"evidence\": \"Exome sequencing, calcium imaging, phase separation and stress granule assays, Co-IP in motor neuron cells and patient brain tissue\",\n      \"pmids\": [\"33087501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Ca²⁺-dependent conformational change unknown\", \"Whether stress granule defects are cause or consequence of neurodegeneration unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Patient-derived fibroblasts carrying P36R and D40G mutations validated that impaired calcium homeostasis, defective stress granule disassembly, and impaired protein translation are cell-autonomous consequences of these variants.\",\n      \"evidence\": \"Patient fibroblast calcium imaging, stress granule dynamics, and translation assays\",\n      \"pmids\": [\"36458208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Fibroblasts rather than neurons used\", \"Translation impairment mechanism not defined at molecular level\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Biochemical reconstitution showed that the D40I variant is even more aggregation-prone than D40G, establishing a graded spectrum of phase separation defects at the Asp40 position and confirming stress granule dysfunction in patient tissue.\",\n      \"evidence\": \"Recombinant protein phase separation assays, patient fibroblast stress granule assays, muscle biopsy histopathology\",\n      \"pmids\": [\"36651622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative relationship between aggregation propensity and disease severity not established\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The landmark discovery that ANXA11 and TDP-43 co-assemble into heteromeric amyloid filaments in FTLD-TDP type C brains, with an extensive hydrophobic interface between their low-complexity domains, fundamentally redefined the pathological role of ANXA11 from a bystander to a structural co-component of disease-defining inclusions.\",\n      \"evidence\": \"Cryo-EM of patient brain-derived filaments at atomic resolution, immunoblotting, immunohistochemistry\",\n      \"pmids\": [\"39260416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether heteromeric filaments form in ALS as well as FTLD-TDP type C is unknown\", \"Mechanism of N-terminal cleavage generating the ~22 kDa fragment is unidentified\", \"Whether co-assembly is required for toxicity or is an end-stage phenomenon unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ANXA11 was established as a non-canonical RNA-binding protein that binds miR-148a-3p in a sequence-specific manner, with its intracellular retention of miRNA modulating extracellular vesicle-mediated chemoresistance signaling.\",\n      \"evidence\": \"RNA pull-down, mass spectrometry, EMSA, microRNA FISH, in vivo xenograft\",\n      \"pmids\": [\"39259536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding specificity determinants in ANXA11 not mapped\", \"Generality of miRNA regulation beyond miR-148a-3p unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"iPSC-derived neuron studies with the P93S variant demonstrated that ANXA11 mutations decrease lysosome–RNA granule co-localization, reduce neuritic RNA, and cause nuclear TDP-43 loss with cryptic exon expression, directly linking the tethering function to TDP-43 nuclear biology.\",\n      \"evidence\": \"iPSC-derived neurons, immunofluorescence, HCR FISH for cryptic exons\",\n      \"pmids\": [\"38923692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from lysosome–RNA granule uncoupling to TDP-43 nuclear loss not mechanistically resolved\", \"Single mutation studied\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The P36R knock-in mouse model provided the first in vivo demonstration that mutant ANXA11 causes progressive TDP-43 and p62-positive co-aggregation, autophagy impairment via mTORC1 hyperactivation, motor neuron loss, and neuroinflammation, establishing a gain-of-function disease mechanism.\",\n      \"evidence\": \"Knock-in mouse model with longitudinal analysis at 2 and 9 months, electron microscopy, autophagic flux assays\",\n      \"pmids\": [\"39755715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ANXA11 aggregates impair autophagy and activate mTORC1 at the molecular level is undefined\", \"Whether motor phenotype fully recapitulates ALS not assessed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The physiological tethering function was mechanistically elaborated: ANXA11's N-terminal phase separation induces coupled phase state changes in lysosomal membrane lipids, and the interacting proteins ALG2 and CALC regulate this phase coupling and the nanomechanical properties of the ANXA11–lysosome ensemble.\",\n      \"evidence\": \"Live-cell imaging, Co-IP, biophysical membrane nanomechanics assays, phase separation assays\",\n      \"pmids\": [\"40118863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of ALG2/CALC regulation of ANXA11 phase coupling not resolved\", \"How membrane lipid phase changes influence RNP granule engagement is not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of full-length ANXA11's Ca²⁺-dependent conformational switch at atomic resolution, the protease responsible for generating the ~22 kDa N-terminal fragment found in FTLD filaments, and whether ANXA11–TDP-43 heteromeric amyloid formation is a cause or consequence of neurodegeneration.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of full-length ANXA11 in either conformational state\", \"Identity of the protease generating the pathological N-terminal fragment is unknown\", \"Causal versus consequential role of heteromeric amyloid filaments in disease not tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [\n      \"ANXA11–TDP-43 heteromeric amyloid filament\"\n    ],\n    \"partners\": [\n      \"TDP43\",\n      \"ALG2\",\n      \"FUS\",\n      \"HNRNPA1\",\n      \"CEP55\",\n      \"CHMP2B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}