{"gene":"IDE","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2007,"finding":"Crystal structure of substrate-free human IDE in closed conformation reveals the molecular details of the active catalytic site and how the closed conformation keeps IDE in a resting, inactive state. Destabilizing mutations at the IDE-N/IDE-C interface (D426C and K899C) increase Vmax for Aβ degradation with minimal Km change, demonstrating that the conformational switch from closed to open is rate-limiting. ATP was shown to induce an increase in hydrodynamic radius, a shift in electrophoretic mobility, and changes in secondary structure, supporting a mechanism whereby ATP facilitates the transition from closed to open conformation.","method":"X-ray crystallography of substrate-free IDE; active-site interface mutagenesis with in vitro kinetic assays; biophysical analysis (dynamic light scattering, native PAGE, CD spectroscopy) of ATP-induced conformational change","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and multiple orthogonal biophysical methods in one rigorous study","pmids":["17613531"],"is_preprint":false},{"year":2010,"finding":"Deletion of the dimer interface in the C-terminal region of IDE yields a monomeric variant that retains enzymatic activity but displays Michaelis-Menten (non-allosteric) kinetics instead of the sigmoidal allosteric behavior of wild-type IDE. Monomeric IDE retains ~25% activity on a small fluorescent peptide substrate but only 0.25–1% of wild-type activity on large peptide substrates (β-endorphin, Aβ1-40). Neither bradykinin, dynorphin B-9, nor polyphosphates activate monomeric IDE, establishing that oligomerization (dimer interface) is required for IDE's regulatory/allosteric properties and that activator binding induces a conformational change that cannot occur in the monomer.","method":"Site-directed mutagenesis to delete dimer interface; size-exclusion chromatography to confirm monomer; in vitro kinetic assays with multiple substrates; activator dose-response assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with mutagenesis, multiple substrates and activators tested, single lab but orthogonal methods","pmids":["20300529"],"is_preprint":false},{"year":2008,"finding":"Endogenous IDE from brain tissue and cultured cells associates with detergent-resistant membranes (DRMs/lipid rafts) in addition to cytosolic localization. Live immunofluorescence, immuno-gold electron microscopy, and gradient fractionation demonstrate two IDE pools: cytosolic (longer half-life) and membrane-associated (faster turnover). Disruption of DRM integrity by methyl-β-cyclodextrin (MβCD) mislocalizes IDE away from DRMs, causing extracellular Aβ accumulation and impairing both exogenous Aβ and insulin degradation. Reduction of cholesterol in vivo (seladin-1 heterozygous knockout mice) also reduces DRM-associated IDE and diminishes IDE-mediated substrate degradation.","method":"Live immunofluorescence; immuno-gold electron microscopy; sucrose density gradient fractionation; pulse-chase turnover assays; MβCD-mediated cholesterol depletion; seladin-1 KO mouse model; in vitro Aβ/insulin degradation assays","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal localization methods (live IF, EM, fractionation) combined with functional consequence (substrate accumulation) and in vivo genetic model","pmids":["19117523"],"is_preprint":false},{"year":2011,"finding":"Notch target transcription factors HES-1 and Hey-1 directly bind to two functional sites in the IDE proximal promoter (at positions −379/−372 and −310/−303 from the first translation start site) and repress IDE transcription and enzymatic activity. Transient transfection of Notch intracellular domain (NICD) in N2aSW neuroblastoma cells reduces IDE mRNA levels and promotes extracellular Aβ accumulation. Site-directed mutagenesis of these two promoter sites reverses NICD-mediated IDE repression. Intracranial injection of the Notch ligand JAG-1 in Tg2576 AD mice induces HES-1/Hey-1 overexpression and reduces IDE mRNA, linking Notch signaling to IDE-mediated Aβ metabolism in vivo.","method":"Luciferase promoter reporter assays; site-directed mutagenesis of IDE promoter; transient transfection of NICD, HES-1, Hey-1; qRT-PCR for IDE mRNA; in vivo JAG-1 intracranial injection in Tg2576 mice; Aβ ELISA","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — promoter mutagenesis plus rescue, in vitro and in vivo validation, single lab with multiple orthogonal methods","pmids":["22036964"],"is_preprint":false},{"year":2012,"finding":"IDE is upregulated in a heat shock protein (HSP)-like manner in normal and malignant cells exposed to various stresses. IDE-silencing in neuroblastoma (SH-SY5Y) cells inhibits cell proliferation and triggers cell death. IDE co-immunoprecipitates with proteasome components and ubiquitin in SH-SY5Y cells, and IDE inhibition is accompanied by a decrease in poly-ubiquitinated protein content, suggesting IDE participates in ubiquitin/proteasome protein quality control.","method":"Stress-induced IDE expression analysis; siRNA knockdown with cell proliferation and viability assays; co-immunoprecipitation of IDE with proteasome and ubiquitin; western blotting for poly-ubiquitinated proteins","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP and KD phenotype in single lab, two orthogonal approaches, but mechanistic follow-up is partial","pmids":["23188819"],"is_preprint":false},{"year":2011,"finding":"BRI2 (ITM2B) overexpression reduces extracellular Aβ levels by increasing the levels of secreted IDE, a major Aβ-degrading protease. This effect is observed with both wild-type BRI2 and its disease-associated mutant ADanPP, and is retained by BRI2 lacking its C-terminal 23-amino acid peptide, indicating BRI2 acts as a regulatory protein modulating extracellular IDE levels to influence Aβ metabolism.","method":"BRI2/ADanPP overexpression in cells; Aβ ELISA of conditioned medium; western blot and ELISA for secreted IDE; BRI2 C-terminal truncation constructs; AD mouse model plaque load assessment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple constructs and in vivo mouse model, single lab, mechanistic follow-up identifies IDE as mediator but does not resolve binding mechanism","pmids":["21873424"],"is_preprint":false},{"year":2013,"finding":"Ide knockout (KO) mice exhibit decreased glucose-stimulated insulin secretion (GSIS) due to impaired replenishment of the releasable pool of insulin granules, and the Ide gene is haploinsufficient for this phenotype. Autophagic flux and microtubule content are reduced in β-cells of Ide KO mice. IDE and α-synuclein levels are inversely correlated in β-cells of Ide KO mice and T2D patients, and both gain and loss of function of α-synuclein in β-cells in vivo impair GSIS and autophagy, establishing IDE as a regulator of β-cell function through control of amyloidogenic α-synuclein levels.","method":"Ide KO and haploinsufficient mouse models; in vivo GSIS assays; autophagy flux assays; immunofluorescence for microtubules; quantitative IDE and α-synuclein protein measurements; α-synuclein gain/loss-of-function transgenic models in vivo","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic mouse models with defined cellular phenotypes, haploinsufficiency confirmed, mechanistic pathway (IDE→α-synuclein→autophagy→GSIS) validated in vivo","pmids":["23349488"],"is_preprint":false},{"year":2019,"finding":"SIRT4 interacts with PTEN and facilitates its degradation through IDE via the lysosomal pathway in response to nutritional starvation. SIRT4 bridges PTEN and IDE for degradation independently of PTEN acetylation or ubiquitination. Overexpression of SIRT4 causes down-regulation of PTEN, and this regulation is abrogated when IDE is inhibited, establishing IDE as a lysosomal protease mediating SIRT4-dependent PTEN degradation under stress conditions.","method":"Co-immunoprecipitation of SIRT4 with PTEN and IDE; SIRT4 overexpression with PTEN protein quantification; IDE inhibition rescue experiments; lysosome pathway inhibitors; nutritional starvation stress conditions","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP and pathway rescue by IDE inhibition, single lab, two orthogonal approaches","pmids":["30649986"],"is_preprint":false},{"year":2017,"finding":"Sorting nexin 5 (SNX5) co-localizes with IDE at the plasma membrane and perinuclear area in human renal proximal tubule cells (hRPTCs) and in the brush border membrane of proximal tubules. Insulin increases co-localization and co-immunoprecipitation of SNX5 and IDE. Silencing SNX5 in hRPTCs decreases IDE expression and activity. Renal-selective silencing of Snx5 in mice decreases IDE protein and urinary insulin excretion, impairs insulin/glucose responses, and increases blood insulin and glucose, establishing SNX5 as a positive regulator of IDE expression and function in the kidney.","method":"Co-immunofluorescence localization; co-immunoprecipitation; siRNA knockdown in hRPTCs with IDE activity assays; renal-selective in vivo Snx5 silencing via osmotic mini-pump; glucose/insulin tolerance tests; spontaneously hypertensive rat (SHR) comparisons","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, co-localization, and in vivo genetic knockdown with defined metabolic phenotype, replicated in two rodent models","pmids":["29080975"],"is_preprint":false},{"year":2009,"finding":"ApoE4, compared to ApoE2 and ApoE3, significantly reduces IDE protein levels in hippocampal neurons. This reduction is blocked by NMDA receptor inhibitors and by RAP (receptor-associated protein, blocking LDL receptor family interactions), indicating ApoE4 acts through its receptor to stimulate the NMDA receptor pathway. Inhibition of NMDA receptor increases IDE levels, while NMDA receptor activation decreases IDE expression. The cAMP-dependent protein kinase (PKA) pathway acts downstream of the NMDA receptor to mediate NMDA-induced IDE repression.","method":"ApoE isoform treatment of primary hippocampal neurons; NMDA receptor inhibitors and activators; RAP blockade; PKA inhibitor/activator pharmacology; western blotting for IDE protein","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological pathway dissection with multiple inhibitors, single lab, consistent results across orthogonal receptor-blocking approaches","pmids":["19616072"],"is_preprint":false},{"year":2010,"finding":"A previously unreported IDE promoter SNP, rs6583817, is unequivocally associated with increased IDE transcript levels in human cerebella (p=1.5×10⁻⁸, fold-increase=2.12). In vitro dual luciferase reporter assays confirm rs6583817 increases reporter gene expression in Be(2)-C and HepG2 cell lines. A proxy for rs6583817 is associated with decreased plasma Aβ40 levels in a population cohort, and rs6583817 is associated with decreased risk of late-onset Alzheimer's disease, establishing a functional regulatory variant in the IDE promoter that links IDE expression level to Aβ metabolism.","method":"Dual luciferase reporter assay in two cell lines; eQTL analysis of IDE transcript levels in 194 LOAD cerebella; GWAS proxy analysis for plasma Aβ40; case-control association in 3,891 AD cases and 3,605 controls","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional reporter assay plus eQTL plus population genetics, single study but three orthogonal approaches","pmids":["20098734"],"is_preprint":false},{"year":2023,"finding":"In IDE knockout (IDE-KO) mice, specific microgliosis is induced in the hippocampus without effects on hippocampal volume or astrogliosis, revealing a non-enzymatic role for IDE in regulating microglial phenotype. Primary microglial cultures from IDE-KO mice show impaired modulation of phenotypic states in response to environmental signals, with only transitory effects on Aβ management, indicating that IDE's microglial function cannot be explained solely by its proteolytic activity.","method":"IDE-KO mouse model; immunohistochemistry for microglia and astrocytes; hippocampal volume measurement; behavioral memory testing; primary microglial culture from wildtype and IDE-KO mice with functional phenotyping assays","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined KO phenotype with primary cell culture validation, single lab, multiple cellular readouts","pmids":["37817156"],"is_preprint":false}],"current_model":"IDE is a zinc metalloprotease that adopts a dimer-dependent allosteric mechanism: the enzyme alternates between a closed (inactive) and open (active) conformation, with the rate-limiting step being this conformational transition; ATP and activating molecules facilitate opening, the dimer interface is required for allosteric regulation, and substrate degradation (insulin, Aβ, PTEN, and other amyloidogenic peptides) is optimized when IDE is associated with detergent-resistant membrane microdomains. IDE expression is transcriptionally repressed by Notch-activated factors HES-1/Hey-1 and by the NMDA receptor/PKA pathway downstream of ApoE4, and is positively regulated by SNX5 in the kidney; in β-cells, IDE controls glucose-stimulated insulin secretion by degrading α-synuclein and maintaining autophagic flux, while under nutritional stress SIRT4 recruits IDE to lysosomal degradation of PTEN."},"narrative":{"mechanistic_narrative":"IDE is a zinc metalloprotease that degrades insulin, amyloid-β (Aβ), and other peptide substrates through a dimer-dependent allosteric mechanism in which a rate-limiting conformational switch between a closed (inactive) and open (active) state governs catalysis [PMID:17613531]. Crystallographic and biophysical analysis established that substrate-free IDE rests in the closed state, that destabilizing the IDE-N/IDE-C interface accelerates Aβ turnover by increasing Vmax, and that ATP facilitates the closed-to-open transition [PMID:17613531]; deletion of the C-terminal dimer interface abolishes allosteric (sigmoidal) kinetics and the ability of small activators to stimulate large-substrate degradation, demonstrating that oligomerization is required for IDE's regulatory behavior [PMID:20300529]. Efficient degradation of extracellular Aβ and insulin depends on a membrane-associated IDE pool localized to detergent-resistant membrane microdomains, the integrity of which is cholesterol-dependent [PMID:19117523]. IDE expression is tightly controlled at the transcriptional level: the Notch effectors HES-1 and Hey-1 bind the IDE proximal promoter and repress its transcription and activity, linking Notch signaling to Aβ metabolism in vivo [PMID:22036964], a functional promoter variant (rs6583817) raises IDE transcript levels and associates with lower plasma Aβ40 and reduced late-onset Alzheimer's disease risk [PMID:20098734], and ApoE4 lowers neuronal IDE through an NMDA-receptor/PKA pathway [PMID:19616072]. Beyond Aβ clearance, IDE controls β-cell function by degrading α-synuclein to sustain autophagic flux and glucose-stimulated insulin secretion [PMID:23349488], mediates SIRT4-bridged lysosomal degradation of PTEN under nutritional stress [PMID:30649986], and is positively regulated by SNX5 to control renal insulin handling [PMID:29080975]. IDE additionally has a non-enzymatic role in shaping microglial phenotype in the hippocampus [PMID:37817156].","teleology":[{"year":2007,"claim":"Establishing how IDE catalysis is regulated, the closed crystal structure plus interface mutagenesis showed the closed-to-open conformational switch is the rate-limiting step and that ATP promotes opening.","evidence":"X-ray crystallography of substrate-free IDE, interface mutagenesis with in vitro kinetics, and biophysical analysis of ATP-induced conformational change","pmids":["17613531"],"confidence":"High","gaps":["Did not resolve a substrate-bound open-state structure","Physiological trigger that promotes opening in cells not defined"]},{"year":2008,"claim":"Resolving where active IDE operates, endogenous IDE was shown to partition between cytosol and cholesterol-dependent detergent-resistant membranes required for efficient Aβ and insulin degradation.","evidence":"Live immunofluorescence, immuno-gold EM, density-gradient fractionation, MβCD cholesterol depletion, and seladin-1 KO mice with degradation assays","pmids":["19117523"],"confidence":"High","gaps":["Mechanism of IDE targeting to DRMs unknown","No membrane-anchoring partner identified"]},{"year":2010,"claim":"Testing whether oligomerization underlies allosteric regulation, a monomeric IDE variant retained basal activity but lost sigmoidal kinetics and activator responsiveness, proving the dimer interface is required for regulation.","evidence":"Dimer-interface deletion mutagenesis, size-exclusion chromatography, and kinetic/activator assays across multiple substrates","pmids":["20300529"],"confidence":"High","gaps":["Endogenous oligomeric state in cells not quantified","Physiological allosteric activators not identified"]},{"year":2009,"claim":"Connecting an Alzheimer's risk factor to IDE, ApoE4 was shown to repress neuronal IDE via an LDL-receptor-family/NMDA-receptor/PKA pathway.","evidence":"ApoE isoform treatment of primary hippocampal neurons with NMDA-receptor and PKA pharmacology, RAP blockade, and IDE western blotting","pmids":["19616072"],"confidence":"Medium","gaps":["Transcription factor executing PKA-dependent repression not identified","Pharmacology not confirmed with genetic perturbation"]},{"year":2010,"claim":"Linking IDE expression level to disease risk, a functional promoter SNP (rs6583817) was shown to raise IDE transcription and associate with lower plasma Aβ40 and reduced LOAD risk.","evidence":"Dual luciferase reporter assays, cerebellar eQTL analysis, GWAS proxy for plasma Aβ40, and case-control association","pmids":["20098734"],"confidence":"Medium","gaps":["Transcription factor binding the variant not identified","Causal contribution to brain Aβ not directly shown"]},{"year":2011,"claim":"Defining a transcriptional repressor of IDE, Notch effectors HES-1/Hey-1 were shown to bind the IDE promoter and repress its expression, coupling Notch signaling to Aβ accumulation.","evidence":"Promoter luciferase reporter with site-directed mutagenesis, NICD/HES-1/Hey-1 transfection, qRT-PCR, and JAG-1 intracranial injection in Tg2576 mice","pmids":["22036964"],"confidence":"High","gaps":["Direct promoter occupancy not shown by ChIP","Interplay with other IDE regulators not addressed"]},{"year":2011,"claim":"Identifying a regulator of extracellular IDE, BRI2 (ITM2B) overexpression was shown to increase secreted IDE and lower extracellular Aβ.","evidence":"BRI2/ADanPP and truncation construct overexpression, conditioned-medium Aβ and IDE ELISA/western, and AD mouse plaque assessment","pmids":["21873424"],"confidence":"Medium","gaps":["Direct BRI2-IDE binding not resolved","Mechanism of IDE secretion not defined"]},{"year":2012,"claim":"Probing a proteostasis role, stress-inducible IDE was found to associate with proteasome components and ubiquitin and to be required for cell survival and poly-ubiquitinated protein levels.","evidence":"Stress-induction analysis, siRNA knockdown viability assays, and co-IP of IDE with proteasome/ubiquitin in SH-SY5Y cells","pmids":["23188819"],"confidence":"Medium","gaps":["Direct enzymatic substrate in this pathway not identified","Co-IP not reciprocally validated"]},{"year":2013,"claim":"Establishing IDE's role in β-cell physiology, Ide-KO mice showed impaired glucose-stimulated insulin secretion via accumulation of α-synuclein and reduced autophagic flux.","evidence":"Ide KO/haploinsufficient mice, in vivo GSIS and autophagy assays, and α-synuclein gain/loss-of-function transgenic models","pmids":["23349488"],"confidence":"High","gaps":["Whether IDE degrades α-synuclein directly in β-cells not biochemically isolated","Link between autophagy defect and granule pool not fully mechanistic"]},{"year":2017,"claim":"Identifying a positive regulator, SNX5 was shown to co-localize with and bind IDE and to maintain renal IDE expression/activity controlling insulin handling.","evidence":"Co-immunofluorescence, reciprocal co-IP, siRNA knockdown in hRPTCs, and renal-selective Snx5 silencing in mice with metabolic phenotyping","pmids":["29080975"],"confidence":"High","gaps":["Mechanism by which SNX5 stabilizes IDE not defined","Generalization beyond kidney not established"]},{"year":2019,"claim":"Extending IDE to a new substrate pathway, SIRT4 was shown to bridge PTEN to IDE for lysosomal degradation under nutritional stress.","evidence":"Reciprocal co-IP of SIRT4/PTEN/IDE, SIRT4 overexpression with PTEN quantification, IDE inhibition rescue, and lysosomal pathway inhibitors","pmids":["30649986"],"confidence":"Medium","gaps":["Direct IDE-mediated PTEN cleavage not reconstituted","How cytosolic/membrane IDE accesses lysosomal substrate unclear"]},{"year":2023,"claim":"Revealing a non-proteolytic function, IDE-KO mice exhibited hippocampal microgliosis and impaired microglial phenotype modulation not explained by Aβ degradation.","evidence":"IDE-KO mouse immunohistochemistry, behavioral testing, and primary microglial cultures with functional phenotyping","pmids":["37817156"],"confidence":"Medium","gaps":["Molecular basis of the non-enzymatic microglial role unknown","Relevant IDE-binding partner in microglia not identified"]},{"year":null,"claim":"How IDE's catalytic conformational cycle, membrane localization, and diverse transcriptional/post-translational regulators are integrated to direct substrate choice across insulin, Aβ, α-synuclein, and PTEN remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking allosteric state to substrate selectivity in vivo","Determinants of cytosolic vs membrane vs lysosomal substrate access unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[7]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,10]}],"complexes":[],"partners":["SNX5","SIRT4","PTEN","ITM2B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14735","full_name":"Insulin-degrading enzyme","aliases":["Abeta-degrading protease","Insulin protease","Insulinase","Insulysin"],"length_aa":1019,"mass_kda":118.0,"function":"Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, natriuretic peptides, glucagon, bradykinin, kallidin, and other peptides, and thereby plays a role in intercellular peptide signaling (PubMed:10684867, PubMed:17051221, PubMed:17613531, PubMed:18986166, PubMed:19321446, PubMed:21098034, PubMed:2293021, PubMed:23922390, PubMed:24847884, PubMed:26394692, PubMed:26968463, PubMed:29596046). Substrate binding induces important conformation changes, making it possible to bind and degrade larger substrates, such as insulin (PubMed:23922390, PubMed:26394692, PubMed:29596046). Contributes to the regulation of peptide hormone signaling cascades and regulation of blood glucose homeostasis via its role in the degradation of insulin, glucagon and IAPP (By similarity). Plays a role in the degradation and clearance of APP-derived amyloidogenic peptides that are secreted by neurons and microglia (Probable) (PubMed:26394692, PubMed:9830016). Degrades the natriuretic peptides ANP, BNP and CNP, inactivating their ability to raise intracellular cGMP (PubMed:21098034). Also degrades an aberrant frameshifted 40-residue form of NPPA (fsNPPA) which is associated with familial atrial fibrillation in heterozygous patients (PubMed:21098034). Involved in antigen processing. Produces both the N terminus and the C terminus of MAGEA3-derived antigenic peptide (EVDPIGHLY) that is presented to cytotoxic T lymphocytes by MHC class I (Microbial infection) The membrane-associated isoform acts as an entry receptor for varicella-zoster virus (VZV)","subcellular_location":"Cytoplasm, cytosol; Cell membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/P14735/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IDE","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IDE","total_profiled":1310},"omim":[{"mim_id":"620997","title":"SEMAPHORIN 3G; SEMA3G","url":"https://www.omim.org/entry/620997"},{"mim_id":"620764","title":"MITOCHONDRIAL SHEATH FORMATION-ASSOCIATED; MISFA","url":"https://www.omim.org/entry/620764"},{"mim_id":"619534","title":"BILIARY, RENAL, NEUROLOGIC, AND SKELETAL SYNDROME; BRENS","url":"https://www.omim.org/entry/619534"},{"mim_id":"618597","title":"BRAIN-ENRICHED GUANYLATE KINASE-ASSOCIATED PROTEIN; BEGAIN","url":"https://www.omim.org/entry/618597"},{"mim_id":"618211","title":"PITRILYSIN METALLOPEPTIDASE 1; PITRM1","url":"https://www.omim.org/entry/618211"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IDE"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P14735","domains":[{"cath_id":"3.30.830.10","chopping":"51-277","consensus_level":"high","plddt":97.752,"start":51,"end":277},{"cath_id":"3.30.830.10","chopping":"296-407_460-516","consensus_level":"high","plddt":98.1046,"start":296,"end":516},{"cath_id":"3.30.830.10","chopping":"550-763","consensus_level":"high","plddt":97.7557,"start":550,"end":763},{"cath_id":"3.30.830.10","chopping":"777-1002","consensus_level":"high","plddt":94.1675,"start":777,"end":1002}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14735","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14735-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14735-F1-predicted_aligned_error_v6.png","plddt_mean":94.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IDE","jax_strain_url":"https://www.jax.org/strain/search?query=IDE"},"sequence":{"accession":"P14735","fasta_url":"https://rest.uniprot.org/uniprotkb/P14735.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14735/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14735"}},"corpus_meta":[{"pmid":"36762851","id":"PMC_36762851","title":"Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma.","date":"2023","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36762851","citation_count":591,"is_preprint":false},{"pmid":"19737565","id":"PMC_19737565","title":"Hepatitis B virus resistance to nucleos(t)ide analogues.","date":"2009","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/19737565","citation_count":564,"is_preprint":false},{"pmid":"18633108","id":"PMC_18633108","title":"Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population.","date":"2008","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/18633108","citation_count":188,"is_preprint":false},{"pmid":"11425794","id":"PMC_11425794","title":"The ins(ide) and out(side) of dolichyl phosphate biosynthesis and recycling in the endoplasmic 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hepatitis","url":"https://pubmed.ncbi.nlm.nih.gov/35274400","citation_count":12,"is_preprint":false},{"pmid":"38432157","id":"PMC_38432157","title":"Rh proteins and H+ transporters involved in ammonia excretion in Amur Ide (Leuciscus waleckii) under high alkali exposure.","date":"2024","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/38432157","citation_count":12,"is_preprint":false},{"pmid":"26876337","id":"PMC_26876337","title":"Prevalence of mutations in HBV DNA polymerase gene associated with nucleos(t)ide resistance in treatment-naive patients with Chronic Hepatitis B in Central China.","date":"2016","source":"The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26876337","citation_count":12,"is_preprint":false},{"pmid":"23121368","id":"PMC_23121368","title":"Tolerability and efficacy of anti-HBV nucleos(t)ide analogues in HBV-DNA-positive cirrhotic patients with HBV/HCV dual infection.","date":"2012","source":"Journal of viral hepatitis","url":"https://pubmed.ncbi.nlm.nih.gov/23121368","citation_count":12,"is_preprint":false},{"pmid":"35889747","id":"PMC_35889747","title":"Arthrospira Enhances Seroclearance in Patients with Chronic Hepatitis B Receiving Nucleos(t)ide Analogue through Modulation of TNF-α/IFN-γ Profile.","date":"2022","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/35889747","citation_count":12,"is_preprint":false},{"pmid":"20669138","id":"PMC_20669138","title":"Therapy with nucleos(t)ide analogues: current role in dialysis patients.","date":"2010","source":"The International journal of artificial organs","url":"https://pubmed.ncbi.nlm.nih.gov/20669138","citation_count":11,"is_preprint":false},{"pmid":"23563307","id":"PMC_23563307","title":"Telbivudine versus entecavir for nucleos(t)ide-naive HBeAg-positive chronic hepatitis B: a meta-analysis.","date":"2014","source":"The American journal of the medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23563307","citation_count":11,"is_preprint":false},{"pmid":"21205143","id":"PMC_21205143","title":"Treatment of HBeAg-positive chronic hepatitis B with nucleos(t)ide analogues.","date":"2011","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/21205143","citation_count":11,"is_preprint":false},{"pmid":"38483300","id":"PMC_38483300","title":"Limited Sustained Remission After Nucleos(t)ide Analog Withdrawal: Results From a Large, Global, Multiethnic Cohort of Patients With Chronic Hepatitis B (RETRACT-B Study).","date":"2024","source":"The American journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/38483300","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":59872,"output_tokens":4560,"usd":0.124008,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12280,"output_tokens":4061,"usd":0.081462,"stage2_stop_reason":"end_turn"},"total_usd":0.20547,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the 100 papers, I need to identify which ones are about the canonical IDE gene (insulin-degrading enzyme, a zinc metalloprotease). Many papers are about \"nucleos(t)ide analogues\" (where \"NA\" appears but not the gene IDE), hepatitis B treatments, CAR T-cell therapy (ide-cel = idecabtagene vicleucel), or other unrelated topics. Let me identify the relevant papers about the IDE protein:\n\n- PMID 17613531: Structure of substrate-free human IDE, conformational switch\n- PMID 23349488: IDE required for insulin secretion, α-synuclein levels in β-cells\n- PMID 19019493: IDE differential deposition in Alzheimer's disease\n- PMID 23188819: IDE as heat shock-like protein, co-IPs with proteasome/ubiquitin\n- PMID 20300529: Monomeric IDE variant loses regulatory properties\n- PMID 21873424: BRI2 increases secreted IDE levels, reduces Aβ\n- PMID 19117523: IDE in detergent-resistant membranes, relevant to Aβ/insulin degradation\n- PMID 22036964: Notch signaling (HES-1, Hey-1) represses IDE transcription\n- PMID 30649986: SIRT4 regulates PTEN stability through IDE\n- PMID 29080975: SNX5 regulates IDE expression/activity in kidney\n- PMID 19616072: ApoE4 reduces IDE via NMDA receptor/PKA pathway\n- PMID 20098734: IDE SNP rs6583817 increases IDE expression, reduces Aβ40\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of substrate-free human IDE in closed conformation reveals the molecular details of the active catalytic site and how the closed conformation keeps IDE in a resting, inactive state. Destabilizing mutations at the IDE-N/IDE-C interface (D426C and K899C) increase Vmax for Aβ degradation with minimal Km change, demonstrating that the conformational switch from closed to open is rate-limiting. ATP was shown to induce an increase in hydrodynamic radius, a shift in electrophoretic mobility, and changes in secondary structure, supporting a mechanism whereby ATP facilitates the transition from closed to open conformation.\",\n      \"method\": \"X-ray crystallography of substrate-free IDE; active-site interface mutagenesis with in vitro kinetic assays; biophysical analysis (dynamic light scattering, native PAGE, CD spectroscopy) of ATP-induced conformational change\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and multiple orthogonal biophysical methods in one rigorous study\",\n      \"pmids\": [\"17613531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Deletion of the dimer interface in the C-terminal region of IDE yields a monomeric variant that retains enzymatic activity but displays Michaelis-Menten (non-allosteric) kinetics instead of the sigmoidal allosteric behavior of wild-type IDE. Monomeric IDE retains ~25% activity on a small fluorescent peptide substrate but only 0.25–1% of wild-type activity on large peptide substrates (β-endorphin, Aβ1-40). Neither bradykinin, dynorphin B-9, nor polyphosphates activate monomeric IDE, establishing that oligomerization (dimer interface) is required for IDE's regulatory/allosteric properties and that activator binding induces a conformational change that cannot occur in the monomer.\",\n      \"method\": \"Site-directed mutagenesis to delete dimer interface; size-exclusion chromatography to confirm monomer; in vitro kinetic assays with multiple substrates; activator dose-response assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with mutagenesis, multiple substrates and activators tested, single lab but orthogonal methods\",\n      \"pmids\": [\"20300529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Endogenous IDE from brain tissue and cultured cells associates with detergent-resistant membranes (DRMs/lipid rafts) in addition to cytosolic localization. Live immunofluorescence, immuno-gold electron microscopy, and gradient fractionation demonstrate two IDE pools: cytosolic (longer half-life) and membrane-associated (faster turnover). Disruption of DRM integrity by methyl-β-cyclodextrin (MβCD) mislocalizes IDE away from DRMs, causing extracellular Aβ accumulation and impairing both exogenous Aβ and insulin degradation. Reduction of cholesterol in vivo (seladin-1 heterozygous knockout mice) also reduces DRM-associated IDE and diminishes IDE-mediated substrate degradation.\",\n      \"method\": \"Live immunofluorescence; immuno-gold electron microscopy; sucrose density gradient fractionation; pulse-chase turnover assays; MβCD-mediated cholesterol depletion; seladin-1 KO mouse model; in vitro Aβ/insulin degradation assays\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal localization methods (live IF, EM, fractionation) combined with functional consequence (substrate accumulation) and in vivo genetic model\",\n      \"pmids\": [\"19117523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Notch target transcription factors HES-1 and Hey-1 directly bind to two functional sites in the IDE proximal promoter (at positions −379/−372 and −310/−303 from the first translation start site) and repress IDE transcription and enzymatic activity. Transient transfection of Notch intracellular domain (NICD) in N2aSW neuroblastoma cells reduces IDE mRNA levels and promotes extracellular Aβ accumulation. Site-directed mutagenesis of these two promoter sites reverses NICD-mediated IDE repression. Intracranial injection of the Notch ligand JAG-1 in Tg2576 AD mice induces HES-1/Hey-1 overexpression and reduces IDE mRNA, linking Notch signaling to IDE-mediated Aβ metabolism in vivo.\",\n      \"method\": \"Luciferase promoter reporter assays; site-directed mutagenesis of IDE promoter; transient transfection of NICD, HES-1, Hey-1; qRT-PCR for IDE mRNA; in vivo JAG-1 intracranial injection in Tg2576 mice; Aβ ELISA\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — promoter mutagenesis plus rescue, in vitro and in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22036964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IDE is upregulated in a heat shock protein (HSP)-like manner in normal and malignant cells exposed to various stresses. IDE-silencing in neuroblastoma (SH-SY5Y) cells inhibits cell proliferation and triggers cell death. IDE co-immunoprecipitates with proteasome components and ubiquitin in SH-SY5Y cells, and IDE inhibition is accompanied by a decrease in poly-ubiquitinated protein content, suggesting IDE participates in ubiquitin/proteasome protein quality control.\",\n      \"method\": \"Stress-induced IDE expression analysis; siRNA knockdown with cell proliferation and viability assays; co-immunoprecipitation of IDE with proteasome and ubiquitin; western blotting for poly-ubiquitinated proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP and KD phenotype in single lab, two orthogonal approaches, but mechanistic follow-up is partial\",\n      \"pmids\": [\"23188819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BRI2 (ITM2B) overexpression reduces extracellular Aβ levels by increasing the levels of secreted IDE, a major Aβ-degrading protease. This effect is observed with both wild-type BRI2 and its disease-associated mutant ADanPP, and is retained by BRI2 lacking its C-terminal 23-amino acid peptide, indicating BRI2 acts as a regulatory protein modulating extracellular IDE levels to influence Aβ metabolism.\",\n      \"method\": \"BRI2/ADanPP overexpression in cells; Aβ ELISA of conditioned medium; western blot and ELISA for secreted IDE; BRI2 C-terminal truncation constructs; AD mouse model plaque load assessment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple constructs and in vivo mouse model, single lab, mechanistic follow-up identifies IDE as mediator but does not resolve binding mechanism\",\n      \"pmids\": [\"21873424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ide knockout (KO) mice exhibit decreased glucose-stimulated insulin secretion (GSIS) due to impaired replenishment of the releasable pool of insulin granules, and the Ide gene is haploinsufficient for this phenotype. Autophagic flux and microtubule content are reduced in β-cells of Ide KO mice. IDE and α-synuclein levels are inversely correlated in β-cells of Ide KO mice and T2D patients, and both gain and loss of function of α-synuclein in β-cells in vivo impair GSIS and autophagy, establishing IDE as a regulator of β-cell function through control of amyloidogenic α-synuclein levels.\",\n      \"method\": \"Ide KO and haploinsufficient mouse models; in vivo GSIS assays; autophagy flux assays; immunofluorescence for microtubules; quantitative IDE and α-synuclein protein measurements; α-synuclein gain/loss-of-function transgenic models in vivo\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic mouse models with defined cellular phenotypes, haploinsufficiency confirmed, mechanistic pathway (IDE→α-synuclein→autophagy→GSIS) validated in vivo\",\n      \"pmids\": [\"23349488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT4 interacts with PTEN and facilitates its degradation through IDE via the lysosomal pathway in response to nutritional starvation. SIRT4 bridges PTEN and IDE for degradation independently of PTEN acetylation or ubiquitination. Overexpression of SIRT4 causes down-regulation of PTEN, and this regulation is abrogated when IDE is inhibited, establishing IDE as a lysosomal protease mediating SIRT4-dependent PTEN degradation under stress conditions.\",\n      \"method\": \"Co-immunoprecipitation of SIRT4 with PTEN and IDE; SIRT4 overexpression with PTEN protein quantification; IDE inhibition rescue experiments; lysosome pathway inhibitors; nutritional starvation stress conditions\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP and pathway rescue by IDE inhibition, single lab, two orthogonal approaches\",\n      \"pmids\": [\"30649986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sorting nexin 5 (SNX5) co-localizes with IDE at the plasma membrane and perinuclear area in human renal proximal tubule cells (hRPTCs) and in the brush border membrane of proximal tubules. Insulin increases co-localization and co-immunoprecipitation of SNX5 and IDE. Silencing SNX5 in hRPTCs decreases IDE expression and activity. Renal-selective silencing of Snx5 in mice decreases IDE protein and urinary insulin excretion, impairs insulin/glucose responses, and increases blood insulin and glucose, establishing SNX5 as a positive regulator of IDE expression and function in the kidney.\",\n      \"method\": \"Co-immunofluorescence localization; co-immunoprecipitation; siRNA knockdown in hRPTCs with IDE activity assays; renal-selective in vivo Snx5 silencing via osmotic mini-pump; glucose/insulin tolerance tests; spontaneously hypertensive rat (SHR) comparisons\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, co-localization, and in vivo genetic knockdown with defined metabolic phenotype, replicated in two rodent models\",\n      \"pmids\": [\"29080975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ApoE4, compared to ApoE2 and ApoE3, significantly reduces IDE protein levels in hippocampal neurons. This reduction is blocked by NMDA receptor inhibitors and by RAP (receptor-associated protein, blocking LDL receptor family interactions), indicating ApoE4 acts through its receptor to stimulate the NMDA receptor pathway. Inhibition of NMDA receptor increases IDE levels, while NMDA receptor activation decreases IDE expression. The cAMP-dependent protein kinase (PKA) pathway acts downstream of the NMDA receptor to mediate NMDA-induced IDE repression.\",\n      \"method\": \"ApoE isoform treatment of primary hippocampal neurons; NMDA receptor inhibitors and activators; RAP blockade; PKA inhibitor/activator pharmacology; western blotting for IDE protein\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological pathway dissection with multiple inhibitors, single lab, consistent results across orthogonal receptor-blocking approaches\",\n      \"pmids\": [\"19616072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A previously unreported IDE promoter SNP, rs6583817, is unequivocally associated with increased IDE transcript levels in human cerebella (p=1.5×10⁻⁸, fold-increase=2.12). In vitro dual luciferase reporter assays confirm rs6583817 increases reporter gene expression in Be(2)-C and HepG2 cell lines. A proxy for rs6583817 is associated with decreased plasma Aβ40 levels in a population cohort, and rs6583817 is associated with decreased risk of late-onset Alzheimer's disease, establishing a functional regulatory variant in the IDE promoter that links IDE expression level to Aβ metabolism.\",\n      \"method\": \"Dual luciferase reporter assay in two cell lines; eQTL analysis of IDE transcript levels in 194 LOAD cerebella; GWAS proxy analysis for plasma Aβ40; case-control association in 3,891 AD cases and 3,605 controls\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional reporter assay plus eQTL plus population genetics, single study but three orthogonal approaches\",\n      \"pmids\": [\"20098734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In IDE knockout (IDE-KO) mice, specific microgliosis is induced in the hippocampus without effects on hippocampal volume or astrogliosis, revealing a non-enzymatic role for IDE in regulating microglial phenotype. Primary microglial cultures from IDE-KO mice show impaired modulation of phenotypic states in response to environmental signals, with only transitory effects on Aβ management, indicating that IDE's microglial function cannot be explained solely by its proteolytic activity.\",\n      \"method\": \"IDE-KO mouse model; immunohistochemistry for microglia and astrocytes; hippocampal volume measurement; behavioral memory testing; primary microglial culture from wildtype and IDE-KO mice with functional phenotyping assays\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined KO phenotype with primary cell culture validation, single lab, multiple cellular readouts\",\n      \"pmids\": [\"37817156\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IDE is a zinc metalloprotease that adopts a dimer-dependent allosteric mechanism: the enzyme alternates between a closed (inactive) and open (active) conformation, with the rate-limiting step being this conformational transition; ATP and activating molecules facilitate opening, the dimer interface is required for allosteric regulation, and substrate degradation (insulin, Aβ, PTEN, and other amyloidogenic peptides) is optimized when IDE is associated with detergent-resistant membrane microdomains. IDE expression is transcriptionally repressed by Notch-activated factors HES-1/Hey-1 and by the NMDA receptor/PKA pathway downstream of ApoE4, and is positively regulated by SNX5 in the kidney; in β-cells, IDE controls glucose-stimulated insulin secretion by degrading α-synuclein and maintaining autophagic flux, while under nutritional stress SIRT4 recruits IDE to lysosomal degradation of PTEN.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IDE is a zinc metalloprotease that degrades insulin, amyloid-β (Aβ), and other peptide substrates through a dimer-dependent allosteric mechanism in which a rate-limiting conformational switch between a closed (inactive) and open (active) state governs catalysis [#0]. Crystallographic and biophysical analysis established that substrate-free IDE rests in the closed state, that destabilizing the IDE-N/IDE-C interface accelerates Aβ turnover by increasing Vmax, and that ATP facilitates the closed-to-open transition [#0]; deletion of the C-terminal dimer interface abolishes allosteric (sigmoidal) kinetics and the ability of small activators to stimulate large-substrate degradation, demonstrating that oligomerization is required for IDE's regulatory behavior [#1]. Efficient degradation of extracellular Aβ and insulin depends on a membrane-associated IDE pool localized to detergent-resistant membrane microdomains, the integrity of which is cholesterol-dependent [#2]. IDE expression is tightly controlled at the transcriptional level: the Notch effectors HES-1 and Hey-1 bind the IDE proximal promoter and repress its transcription and activity, linking Notch signaling to Aβ metabolism in vivo [#3], a functional promoter variant (rs6583817) raises IDE transcript levels and associates with lower plasma Aβ40 and reduced late-onset Alzheimer's disease risk [#10], and ApoE4 lowers neuronal IDE through an NMDA-receptor/PKA pathway [#9]. Beyond Aβ clearance, IDE controls β-cell function by degrading α-synuclein to sustain autophagic flux and glucose-stimulated insulin secretion [#6], mediates SIRT4-bridged lysosomal degradation of PTEN under nutritional stress [#7], and is positively regulated by SNX5 to control renal insulin handling [#8]. IDE additionally has a non-enzymatic role in shaping microglial phenotype in the hippocampus [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing how IDE catalysis is regulated, the closed crystal structure plus interface mutagenesis showed the closed-to-open conformational switch is the rate-limiting step and that ATP promotes opening.\",\n      \"evidence\": \"X-ray crystallography of substrate-free IDE, interface mutagenesis with in vitro kinetics, and biophysical analysis of ATP-induced conformational change\",\n      \"pmids\": [\"17613531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve a substrate-bound open-state structure\", \"Physiological trigger that promotes opening in cells not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolving where active IDE operates, endogenous IDE was shown to partition between cytosol and cholesterol-dependent detergent-resistant membranes required for efficient Aβ and insulin degradation.\",\n      \"evidence\": \"Live immunofluorescence, immuno-gold EM, density-gradient fractionation, MβCD cholesterol depletion, and seladin-1 KO mice with degradation assays\",\n      \"pmids\": [\"19117523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of IDE targeting to DRMs unknown\", \"No membrane-anchoring partner identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Testing whether oligomerization underlies allosteric regulation, a monomeric IDE variant retained basal activity but lost sigmoidal kinetics and activator responsiveness, proving the dimer interface is required for regulation.\",\n      \"evidence\": \"Dimer-interface deletion mutagenesis, size-exclusion chromatography, and kinetic/activator assays across multiple substrates\",\n      \"pmids\": [\"20300529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous oligomeric state in cells not quantified\", \"Physiological allosteric activators not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connecting an Alzheimer's risk factor to IDE, ApoE4 was shown to repress neuronal IDE via an LDL-receptor-family/NMDA-receptor/PKA pathway.\",\n      \"evidence\": \"ApoE isoform treatment of primary hippocampal neurons with NMDA-receptor and PKA pharmacology, RAP blockade, and IDE western blotting\",\n      \"pmids\": [\"19616072\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor executing PKA-dependent repression not identified\", \"Pharmacology not confirmed with genetic perturbation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking IDE expression level to disease risk, a functional promoter SNP (rs6583817) was shown to raise IDE transcription and associate with lower plasma Aβ40 and reduced LOAD risk.\",\n      \"evidence\": \"Dual luciferase reporter assays, cerebellar eQTL analysis, GWAS proxy for plasma Aβ40, and case-control association\",\n      \"pmids\": [\"20098734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor binding the variant not identified\", \"Causal contribution to brain Aβ not directly shown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining a transcriptional repressor of IDE, Notch effectors HES-1/Hey-1 were shown to bind the IDE promoter and repress its expression, coupling Notch signaling to Aβ accumulation.\",\n      \"evidence\": \"Promoter luciferase reporter with site-directed mutagenesis, NICD/HES-1/Hey-1 transfection, qRT-PCR, and JAG-1 intracranial injection in Tg2576 mice\",\n      \"pmids\": [\"22036964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct promoter occupancy not shown by ChIP\", \"Interplay with other IDE regulators not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying a regulator of extracellular IDE, BRI2 (ITM2B) overexpression was shown to increase secreted IDE and lower extracellular Aβ.\",\n      \"evidence\": \"BRI2/ADanPP and truncation construct overexpression, conditioned-medium Aβ and IDE ELISA/western, and AD mouse plaque assessment\",\n      \"pmids\": [\"21873424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct BRI2-IDE binding not resolved\", \"Mechanism of IDE secretion not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Probing a proteostasis role, stress-inducible IDE was found to associate with proteasome components and ubiquitin and to be required for cell survival and poly-ubiquitinated protein levels.\",\n      \"evidence\": \"Stress-induction analysis, siRNA knockdown viability assays, and co-IP of IDE with proteasome/ubiquitin in SH-SY5Y cells\",\n      \"pmids\": [\"23188819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic substrate in this pathway not identified\", \"Co-IP not reciprocally validated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing IDE's role in β-cell physiology, Ide-KO mice showed impaired glucose-stimulated insulin secretion via accumulation of α-synuclein and reduced autophagic flux.\",\n      \"evidence\": \"Ide KO/haploinsufficient mice, in vivo GSIS and autophagy assays, and α-synuclein gain/loss-of-function transgenic models\",\n      \"pmids\": [\"23349488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IDE degrades α-synuclein directly in β-cells not biochemically isolated\", \"Link between autophagy defect and granule pool not fully mechanistic\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying a positive regulator, SNX5 was shown to co-localize with and bind IDE and to maintain renal IDE expression/activity controlling insulin handling.\",\n      \"evidence\": \"Co-immunofluorescence, reciprocal co-IP, siRNA knockdown in hRPTCs, and renal-selective Snx5 silencing in mice with metabolic phenotyping\",\n      \"pmids\": [\"29080975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SNX5 stabilizes IDE not defined\", \"Generalization beyond kidney not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extending IDE to a new substrate pathway, SIRT4 was shown to bridge PTEN to IDE for lysosomal degradation under nutritional stress.\",\n      \"evidence\": \"Reciprocal co-IP of SIRT4/PTEN/IDE, SIRT4 overexpression with PTEN quantification, IDE inhibition rescue, and lysosomal pathway inhibitors\",\n      \"pmids\": [\"30649986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IDE-mediated PTEN cleavage not reconstituted\", \"How cytosolic/membrane IDE accesses lysosomal substrate unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealing a non-proteolytic function, IDE-KO mice exhibited hippocampal microgliosis and impaired microglial phenotype modulation not explained by Aβ degradation.\",\n      \"evidence\": \"IDE-KO mouse immunohistochemistry, behavioral testing, and primary microglial cultures with functional phenotyping\",\n      \"pmids\": [\"37817156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the non-enzymatic microglial role unknown\", \"Relevant IDE-binding partner in microglia not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IDE's catalytic conformational cycle, membrane localization, and diverse transcriptional/post-translational regulators are integrated to direct substrate choice across insulin, Aβ, α-synuclein, and PTEN remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking allosteric state to substrate selectivity in vivo\", \"Determinants of cytosolic vs membrane vs lysosomal substrate access unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SNX5\", \"SIRT4\", \"PTEN\", \"ITM2B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}