{"gene":"TMEM163","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2007,"finding":"TMEM163 (SV31) is a synaptic vesicle membrane protein with six putative transmembrane helices, localized to synaptic vesicles as demonstrated by subcellular fractionation, heterologous expression, immunocytochemical analysis of brain sections, and immunoelectron microscopy.","method":"Subcellular fractionation, heterologous expression, immunocytochemistry, immunoelectron microscopy","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing subcellular localization with functional context","pmids":["17623043"],"is_preprint":false},{"year":2011,"finding":"TMEM163 (SV31) binds divalent cations Zn2+ and Ni2+ (and to a minor extent Cu2+), but not Fe2+, Co2+, Mn2+, or Ca2+; in PC12 cells it targets to endosomes and subpopulations of synaptic-like microvesicles.","method":"Metal ion binding assays with recombinant protein, fluorescent zinc indicator (FluoZin-3) in live cells, sucrose density gradient fractionation, immunocytochemistry","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding assay + live-cell fluorescent assay + fractionation, multiple orthogonal methods","pmids":["21668449"],"is_preprint":false},{"year":2014,"finding":"TMEM163 physically interacts with the TRPML1 ion channel; this interaction is disrupted by deletion of part of TMEM163's N-terminus. TRPML1 co-expression reduces plasma membrane levels of TMEM163, and TMEM163 knockdown leads to elevated intracellular zinc levels.","method":"Yeast two-hybrid, co-immunoprecipitation, mass spectrometry, confocal microscopy, N-terminal deletion mutagenesis, fluorescent zinc assays in HEK-293 cells","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, yeast two-hybrid, MS, mutagenesis, and functional zinc assays in one study","pmids":["25130899"],"is_preprint":false},{"year":2016,"finding":"TMEM163 (SV31) assembles into dimers when inserted into nanodisc lipid bilayers; dimerization increases Zn2+ binding capacity. Site-directed mutagenesis of two conserved aspartate residues reduces Zn2+ binding but does not affect dimerization. TMEM163 functions as a proton-dependent Zn2+ transporter (Km ~44.3 μM) as demonstrated by Zn2+ accumulation in proteoliposomes under acidic internal pH.","method":"Cell-free protein synthesis, nanodisc reconstitution, site-directed mutagenesis, native mass spectrometry, proteoliposome transport assay with FluoZin-1","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in proteoliposomes with mutagenesis and transport assay, multiple orthogonal methods","pmids":["27917477"],"is_preprint":false},{"year":2019,"finding":"Human TMEM163 is a zinc efflux transporter; cells expressing TMEM163 show significantly reduced intracellular zinc levels. Alanine substitution of conserved aspartate residues D124A/D128A or the E286K variant significantly reduces zinc efflux, identifying these residues as critical for transport function.","method":"Stable and transient expression in human cell lines, fluorescent zinc dyes (two independent dyes), radionuclide zinc-65 assay, site-directed mutagenesis, TPEN chelator controls","journal":"Archives of biochemistry and biophysics","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro efflux assay with radionuclide + two fluorescent dyes + mutagenesis, multiple orthogonal methods","pmids":["31697912"],"is_preprint":false},{"year":2019,"finding":"Knockdown of Tmem163 in MIN6 pancreatic β-cells increases intracellular zinc and total insulin content but impairs glucose-stimulated insulin secretion, establishing a role for TMEM163 in zinc-regulated insulin storage.","method":"siRNA knockdown in MIN6 cells, zinc measurement, insulin content and secretion assays, glucose uptake assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype, single lab, moderate evidence","pmids":["31813547"],"is_preprint":false},{"year":2020,"finding":"TMEM163 specifically modulates channel properties and pharmacology of ATP-gated P2X receptors (P2XRs); TMEM163 is required for full function of neuronal P2XRs and ATP-evoked pain-related behavior in vivo.","method":"Genome-wide ORF functional screen, electrophysiology, in vivo behavioral assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen plus electrophysiology plus in vivo behavioral validation, strong mechanistic evidence","pmids":["32492420"],"is_preprint":false},{"year":2022,"finding":"TMEM163 forms homodimers and heterodimerizes with ZNT1, ZNT2, ZNT3, and ZNT4; these heterodimers partially co-localize in cells and exhibit similar zinc efflux function as TMEM163 homodimers. Plasma membrane localization of TMEM163 is not markedly altered by ZNT co-expression.","method":"Co-immunoprecipitation, confocal microscopy, functional zinc flux assays (Fluozin-3 and Newport Green), cell surface biotinylation","journal":"Biochemistry and biophysics reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP with functional assay and localization, single lab","pmids":["36204728"],"is_preprint":false},{"year":2022,"finding":"Missense variants in TMEM163 cause hypomyelinating leukodystrophy; mutant proteins show significant impairment in zinc efflux in vitro. Expression of mutant TMEM163 in an oligodendroglial cell line reduces mRNA expression of key myelin genes, reduces branching, and increases cell death.","method":"In vitro zinc efflux assays with patient-derived mutant proteins, oligodendroglial cell line functional assays (branching, apoptosis, myelin gene expression), genomic sequencing","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 — functional zinc efflux assay with disease variants plus cellular phenotype in relevant cell type","pmids":["35953447"],"is_preprint":false},{"year":2022,"finding":"De novo heterozygous variants L76R and L76P in TMEM163 cause hypomyelinating leukodystrophy; L76R attenuates and L76P enhances zinc efflux in HeLa cells. Knockdown of tmem163a/b in zebrafish causes myelin deficit, locomotor disability, and oligodendrocyte apoptosis; human wild-type TMEM163 rescues the phenotype while L76P and L76R mutants aggravate it.","method":"Zinc flux assays in stable HeLa cell lines, zebrafish morphant model with rescue experiments, whole exome sequencing","journal":"Cells","confidence":"High","confidence_rationale":"Tier 2 — in vitro functional assay plus in vivo zebrafish model with rescue, multiple orthogonal methods","pmids":["35455965"],"is_preprint":false},{"year":2024,"finding":"TMEM163 functions as a vesicular Zn2+ transporter in a subset of dorsal root ganglion neurons; in aged mice, TMEM163 expression and vesicular Zn2+ are elevated, and excessive Zn2+ release from TMEM163+ primary afferents dampens NPY+ inhibitory interneuron activity, causing disinhibition of itch-transmitting circuits and chronic itch.","method":"In vivo mouse aging model, Zn2+ imaging, electrophysiology of spinal circuits, Zn2+ chelation in spinal dorsal horn, neuroanatomical tracing","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo functional model with circuit-level electrophysiology and pharmacological rescue, single study","pmids":["39602426"],"is_preprint":false},{"year":2025,"finding":"ZnT3 and TMEM163 physically interact (co-immunoprecipitation) and cooperatively promote zinc efflux in hippocampal neurons; under ischemic (OGD) conditions both proteins translocate from the plasma membrane to the cytoplasm, and their overexpression exacerbates extracellular zinc overload and neuronal apoptosis, while silencing attenuates zinc overload.","method":"Co-immunoprecipitation, cell surface biotinylation, siRNA silencing and plasmid overexpression, FluoZin-3 zinc imaging, TUNEL apoptosis assay, MTT viability assay","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus functional assays with KD/OE, single lab, moderate evidence","pmids":["41504061"],"is_preprint":false},{"year":2026,"finding":"A conserved N-terminal acidic dileucine motif (LEDRGL69L70) in TMEM163 is essential for its interaction with AP-3 and BLOC-1 complexes but dispensable for binding AP-1, AP-2, and BLOC-2. Mutation of this motif causes TMEM163 accumulation at the plasma membrane. Loss of either BLOC-1 or AP-3 enhances TMEM163 binding to the other, suggesting competitive binding during sequential trafficking of TMEM163 to platelet dense granules.","method":"Co-immunoprecipitation, dileucine motif mutagenesis, confocal microscopy of subcellular localization, MEG-01 cell knockouts of endosomal trafficking complexes, proteasome inhibitor assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP with mutagenesis plus localization studies and multiple genetic backgrounds, single study with orthogonal methods","pmids":["41985787"],"is_preprint":false}],"current_model":"TMEM163 is a zinc efflux transporter (designated ZNT11) belonging to the cation diffusion facilitator (CDF)/SLC30 family that localizes to the plasma membrane, lysosomes, early endosomes, and synaptic vesicles; it functions as a proton-dependent, dimer-forming zinc effluxer whose conserved aspartate residues (D124/D128) and E286 are critical for transport activity, it physically interacts with TRPML1, ZNT1/2/3, and ZnT3 to modulate cellular zinc homeostasis, its trafficking to lysosome-related organelles is sequentially governed by AP-3 and BLOC-1 via a dileucine sorting motif, and it additionally modulates P2X receptor channel properties and synaptic zinc signaling relevant to pain and itch circuits."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing that TMEM163 (SV31) is an integral membrane protein of synaptic vesicles resolved its subcellular identity and positioned it as a candidate vesicular transporter or signaling component.","evidence":"Subcellular fractionation, immunocytochemistry, and immunoelectron microscopy in brain tissue and heterologous expression systems","pmids":["17623043"],"confidence":"High","gaps":["No transport function demonstrated","Ligand or substrate unknown","No knockout or knockdown phenotype assessed"]},{"year":2011,"claim":"Demonstrating that TMEM163 selectively binds Zn²⁺ and Ni²⁺ — but not other divalent cations — identified it as a zinc-binding protein and implied a role in zinc homeostasis.","evidence":"Recombinant protein metal-binding assays, FluoZin-3 live-cell imaging, sucrose density gradient fractionation in PC12 cells","pmids":["21668449"],"confidence":"High","gaps":["Binding demonstrated but active transport not yet shown","Physiological relevance of Ni²⁺ binding unclear"]},{"year":2014,"claim":"Identifying TRPML1 as a physical interactor revealed that TMEM163 operates within a protein network governing lysosomal/endosomal zinc flux, and TMEM163 knockdown increasing intracellular zinc provided the first loss-of-function evidence for zinc efflux activity.","evidence":"Yeast two-hybrid, reciprocal co-IP, mass spectrometry, N-terminal deletion mutagenesis, fluorescent zinc assays in HEK-293 cells","pmids":["25130899"],"confidence":"High","gaps":["Direction and mechanism of transport not defined","TRPML1 interaction domain on TRPML1 side not mapped"]},{"year":2016,"claim":"Reconstitution in proteoliposomes proved TMEM163 is a bona fide proton-coupled zinc transporter (Km ~44 µM), and nanodisc experiments established that dimerization enhances Zn²⁺ binding, placing it functionally within the CDF/SLC30 family.","evidence":"Cell-free synthesis, nanodisc reconstitution, native mass spectrometry, proteoliposome transport assay with FluoZin-1, site-directed mutagenesis","pmids":["27917477"],"confidence":"High","gaps":["Transport stoichiometry (Zn²⁺:H⁺) not determined","No structural model at atomic resolution"]},{"year":2019,"claim":"Identification of D124, D128, and E286 as essential residues for zinc efflux in human cells, combined with the finding that TMEM163 knockdown in pancreatic β-cells dysregulates insulin storage, defined the molecular determinants of transport and a physiological role in insulin-secreting cells.","evidence":"Site-directed mutagenesis with radionuclide (⁶⁵Zn) and dual fluorescent dye efflux assays; siRNA knockdown in MIN6 cells with insulin content/secretion measurements","pmids":["31697912","31813547"],"confidence":"High","gaps":["In vivo β-cell phenotype in knockout animals not assessed","Whether E286K is a natural variant with clinical consequence was not established at this time"]},{"year":2020,"claim":"A genome-wide functional screen uncovered TMEM163 as a modulator of P2X receptor channel properties, expanding its role beyond zinc transport to regulation of purinergic signaling and ATP-evoked pain behavior.","evidence":"Genome-wide ORF screen, electrophysiology, and in vivo behavioral pain assays in mice","pmids":["32492420"],"confidence":"High","gaps":["Mechanism of P2X modulation (direct binding vs. zinc-dependent) not resolved","Which P2X subunit(s) are the primary physiological targets in vivo unclear"]},{"year":2022,"claim":"Discovery that TMEM163 heterodimerizes with ZNT1–4 established it as an integral member of the ZNT transporter network, and identification of causative missense variants in hypomyelinating leukodystrophy — validated by zebrafish rescue — linked TMEM163 loss-of-function to a human Mendelian disease affecting myelination.","evidence":"Co-IP and zinc flux assays for ZNT interactions; patient variant functional assays in HeLa and oligodendroglial lines; zebrafish morphant model with human mRNA rescue","pmids":["36204728","35953447","35455965"],"confidence":"High","gaps":["Structural basis for ZNT heterodimerization unknown","Why oligodendrocytes are selectively vulnerable to TMEM163 mutations not explained","Genotype–phenotype correlation across different leukodystrophy variants incomplete"]},{"year":2024,"claim":"Demonstrating that TMEM163 loads vesicular zinc in DRG neurons and that age-related upregulation of TMEM163 causes excessive spinal zinc release and chronic itch via disinhibition of NPY⁺ interneurons established a circuit-level role for TMEM163-dependent zinc signaling in somatosensory pathology.","evidence":"In vivo mouse aging model, zinc imaging, spinal cord electrophysiology, zinc chelation rescue","pmids":["39602426"],"confidence":"Medium","gaps":["Causal relationship tested only pharmacologically, not with conditional TMEM163 knockout","Generalizability beyond aged-mouse itch model not shown"]},{"year":2025,"claim":"Cooperative zinc efflux by ZnT3–TMEM163 complexes in hippocampal neurons, and their ischemia-induced internalization with consequent extracellular zinc overload, extended the functional relevance of TMEM163 heterodimers to excitotoxic neuronal injury.","evidence":"Co-IP, surface biotinylation, siRNA/overexpression, FluoZin-3 zinc imaging, TUNEL and MTT assays in oxygen-glucose deprivation model","pmids":["41504061"],"confidence":"Medium","gaps":["Mechanism of ischemia-triggered internalization not determined","In vivo stroke model validation lacking","Single-lab finding without independent replication"]},{"year":2026,"claim":"Mapping the LEDRGL69L70 dileucine motif as the AP-3/BLOC-1 recognition site, and showing competitive sequential binding of these complexes, resolved the trafficking mechanism by which TMEM163 reaches lysosome-related organelles such as platelet dense granules.","evidence":"Dileucine mutagenesis, co-IP with AP and BLOC complexes, confocal localization, MEG-01 knockout lines","pmids":["41985787"],"confidence":"High","gaps":["Whether the same sorting motif governs TMEM163 targeting in neurons not tested","Structural basis of AP-3 vs. BLOC-1 competitive binding not resolved"]},{"year":null,"claim":"No high-resolution structure of TMEM163 exists, the Zn²⁺:H⁺ transport stoichiometry is undefined, the mechanism by which TMEM163 modulates P2X receptor gating (direct binding versus zinc-mediated) is unresolved, and the selective vulnerability of oligodendrocytes to TMEM163 mutations remains unexplained.","evidence":"","pmids":[],"confidence":"High","gaps":["No atomic-resolution structure","Transport stoichiometry undetermined","P2X modulation mechanism unresolved","Oligodendrocyte-selective pathology mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[3,4,8,9,10,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,7,12]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2,12]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[3,4,8,9]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,10]}],"complexes":[],"partners":["MCOLN1","SLC30A1","SLC30A2","SLC30A3","SLC30A4","P2RX"],"other_free_text":[]},"mechanistic_narrative":"TMEM163 is a proton-coupled zinc efflux transporter of the cation diffusion facilitator family that operates at the plasma membrane, synaptic vesicles, endosomes, and lysosome-related organelles to regulate cellular and vesicular zinc homeostasis. It forms homodimers and heterodimers with ZNT-family transporters (ZNT1–4), and conserved aspartate residues (D124/D128) and E286 are critical for zinc transport activity [PMID:27917477, PMID:31697912, PMID:36204728]. TMEM163 physically interacts with TRPML1 to modulate intracellular zinc levels and with P2X receptors to regulate ATP-gated channel properties relevant to pain signaling, and its trafficking to lysosome-related organelles depends on an N-terminal dileucine motif recognized sequentially by AP-3 and BLOC-1 [PMID:25130899, PMID:32492420, PMID:41985787]. Missense variants in TMEM163 cause hypomyelinating leukodystrophy through impaired zinc efflux and oligodendrocyte dysfunction, as demonstrated by patient-derived mutant analysis and zebrafish rescue experiments [PMID:35953447, PMID:35455965]."},"prefetch_data":{"uniprot":{"accession":"Q8TC26","full_name":"Transmembrane protein 163","aliases":[],"length_aa":289,"mass_kda":31.5,"function":"Zinc ion transporter that mediates zinc efflux and plays a crucial role in intracellular zinc homeostasis (PubMed:25130899, PubMed:31697912, PubMed:36204728). Binds the divalent cations Zn(2+), Ni(2+), and to a minor extent Cu(2+) (By similarity). Is a functional modulator of P2X purinoceptors, including P2RX1, P2RX3, P2RX4 and P2RX7 (PubMed:32492420). Plays a role in central nervous system development and is required for myelination, and survival and proliferation of oligodendrocytes (PubMed:35455965)","subcellular_location":"Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane; Early endosome membrane; Late endosome membrane; Lysosome membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8TC26/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM163","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM163","total_profiled":1310},"omim":[{"mim_id":"620243","title":"LEUKODYSTROPHY, HYPOMYELINATING, 25; HLD25","url":"https://www.omim.org/entry/620243"},{"mim_id":"618978","title":"TRANSMEMBRANE PROTEIN 163; TMEM163","url":"https://www.omim.org/entry/618978"},{"mim_id":"605248","title":"MUCOLIPIN 1; MCOLN1","url":"https://www.omim.org/entry/605248"},{"mim_id":"312080","title":"PELIZAEUS-MERZBACHER DISEASE; PMD","url":"https://www.omim.org/entry/312080"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":44.4},{"tissue":"pancreas","ntpm":26.3}],"url":"https://www.proteinatlas.org/search/TMEM163"},"hgnc":{"alias_symbol":["DKFZP566N034","SV31","SLC30A11"],"prev_symbol":[]},"alphafold":{"accession":"Q8TC26","domains":[{"cath_id":"1.20.1510","chopping":"64-285","consensus_level":"high","plddt":85.0009,"start":64,"end":285}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TC26","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TC26-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TC26-F1-predicted_aligned_error_v6.png","plddt_mean":76.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM163","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM163"},"sequence":{"accession":"Q8TC26","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TC26.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TC26/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TC26"}},"corpus_meta":[{"pmid":"25130899","id":"PMC_25130899","title":"Cellular zinc levels are modulated by TRPML1-TMEM163 interaction.","date":"2014","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/25130899","citation_count":51,"is_preprint":false},{"pmid":"31697912","id":"PMC_31697912","title":"Transmembrane 163 (TMEM163) protein effluxes zinc.","date":"2019","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/31697912","citation_count":28,"is_preprint":false},{"pmid":"17623043","id":"PMC_17623043","title":"Identification and characterization of SV31, a novel synaptic vesicle membrane protein and potential transporter.","date":"2007","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17623043","citation_count":28,"is_preprint":false},{"pmid":"28199205","id":"PMC_28199205","title":"The mucolipin-1 (TRPML1) ion channel, transmembrane-163 (TMEM163) protein, and lysosomal zinc handling.","date":"2017","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/28199205","citation_count":22,"is_preprint":false},{"pmid":"21668449","id":"PMC_21668449","title":"SV31 is a Zn2+-binding synaptic vesicle protein.","date":"2011","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21668449","citation_count":20,"is_preprint":false},{"pmid":"27917477","id":"PMC_27917477","title":"The synaptic vesicle protein SV31 assembles into a dimer and transports Zn2.","date":"2016","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27917477","citation_count":18,"is_preprint":false},{"pmid":"32492420","id":"PMC_32492420","title":"TMEM163 Regulates ATP-Gated P2X Receptor and Behavior.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32492420","citation_count":16,"is_preprint":false},{"pmid":"33670071","id":"PMC_33670071","title":"Transmembrane 163 (TMEM163) Protein: A New Member of the Zinc Efflux Transporter Family.","date":"2021","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/33670071","citation_count":16,"is_preprint":false},{"pmid":"35953447","id":"PMC_35953447","title":"Variants in the zinc transporter TMEM163 cause a hypomyelinating leukodystrophy.","date":"2022","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35953447","citation_count":16,"is_preprint":false},{"pmid":"31813547","id":"PMC_31813547","title":"Role of Tmem163 in zinc-regulated insulin storage of MIN6 cells: Functional exploration of an Indian type 2 diabetes GWAS associated gene.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31813547","citation_count":11,"is_preprint":false},{"pmid":"35455965","id":"PMC_35455965","title":"Functional Study of TMEM163 Gene Variants Associated with Hypomyelination Leukodystrophy.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35455965","citation_count":9,"is_preprint":false},{"pmid":"30719275","id":"PMC_30719275","title":"Polymorphisms of ACMSD-TMEM163, MCCC1, and BCKDK-STX1B Are Not Associated with Parkinson's Disease in Taiwan.","date":"2019","source":"Parkinson's disease","url":"https://pubmed.ncbi.nlm.nih.gov/30719275","citation_count":8,"is_preprint":false},{"pmid":"36204728","id":"PMC_36204728","title":"Transmembrane 163 (TMEM163) protein interacts with specific mammalian SLC30 zinc efflux transporter family members.","date":"2022","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/36204728","citation_count":5,"is_preprint":false},{"pmid":"35207731","id":"PMC_35207731","title":"PPARG, TMEM163, UBE2E2, and WFS1 Gene Polymorphisms Are Not Significant Risk Factors for Gestational Diabetes in the Polish Population.","date":"2022","source":"Journal of personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35207731","citation_count":4,"is_preprint":false},{"pmid":"39602426","id":"PMC_39602426","title":"Elevated vesicular Zn2+ in dorsal root ganglion neurons expressing the transporter TMEM163 causes age-associated itchy skin in mice.","date":"2024","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/39602426","citation_count":3,"is_preprint":false},{"pmid":"39352626","id":"PMC_39352626","title":"The role of TMEM163 protein in thyroid microcarcinoma: expression pattern and clinical implications.","date":"2024","source":"Journal of endocrinological investigation","url":"https://pubmed.ncbi.nlm.nih.gov/39352626","citation_count":1,"is_preprint":false},{"pmid":"41985787","id":"PMC_41985787","title":"A dileucine motif in TMEM163 is essential for its binding with both AP-3 and BLOC-1 complex.","date":"2026","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41985787","citation_count":0,"is_preprint":false},{"pmid":"41504061","id":"PMC_41504061","title":"ZnT3-TMEM163 Mediates Zinc Homeostasis Imbalance Induced Neurodegeneration in Hippocampus.","date":"2025","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/41504061","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9870,"output_tokens":3284,"usd":0.039435},"stage2":{"model":"claude-opus-4-6","input_tokens":6652,"output_tokens":2789,"usd":0.154477},"total_usd":0.193912,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"TMEM163 (SV31) is a synaptic vesicle membrane protein with six putative transmembrane helices, localized to synaptic vesicles as demonstrated by subcellular fractionation, heterologous expression, immunocytochemical analysis of brain sections, and immunoelectron microscopy.\",\n      \"method\": \"Subcellular fractionation, heterologous expression, immunocytochemistry, immunoelectron microscopy\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing subcellular localization with functional context\",\n      \"pmids\": [\"17623043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TMEM163 (SV31) binds divalent cations Zn2+ and Ni2+ (and to a minor extent Cu2+), but not Fe2+, Co2+, Mn2+, or Ca2+; in PC12 cells it targets to endosomes and subpopulations of synaptic-like microvesicles.\",\n      \"method\": \"Metal ion binding assays with recombinant protein, fluorescent zinc indicator (FluoZin-3) in live cells, sucrose density gradient fractionation, immunocytochemistry\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding assay + live-cell fluorescent assay + fractionation, multiple orthogonal methods\",\n      \"pmids\": [\"21668449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TMEM163 physically interacts with the TRPML1 ion channel; this interaction is disrupted by deletion of part of TMEM163's N-terminus. TRPML1 co-expression reduces plasma membrane levels of TMEM163, and TMEM163 knockdown leads to elevated intracellular zinc levels.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, mass spectrometry, confocal microscopy, N-terminal deletion mutagenesis, fluorescent zinc assays in HEK-293 cells\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, yeast two-hybrid, MS, mutagenesis, and functional zinc assays in one study\",\n      \"pmids\": [\"25130899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TMEM163 (SV31) assembles into dimers when inserted into nanodisc lipid bilayers; dimerization increases Zn2+ binding capacity. Site-directed mutagenesis of two conserved aspartate residues reduces Zn2+ binding but does not affect dimerization. TMEM163 functions as a proton-dependent Zn2+ transporter (Km ~44.3 μM) as demonstrated by Zn2+ accumulation in proteoliposomes under acidic internal pH.\",\n      \"method\": \"Cell-free protein synthesis, nanodisc reconstitution, site-directed mutagenesis, native mass spectrometry, proteoliposome transport assay with FluoZin-1\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in proteoliposomes with mutagenesis and transport assay, multiple orthogonal methods\",\n      \"pmids\": [\"27917477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human TMEM163 is a zinc efflux transporter; cells expressing TMEM163 show significantly reduced intracellular zinc levels. Alanine substitution of conserved aspartate residues D124A/D128A or the E286K variant significantly reduces zinc efflux, identifying these residues as critical for transport function.\",\n      \"method\": \"Stable and transient expression in human cell lines, fluorescent zinc dyes (two independent dyes), radionuclide zinc-65 assay, site-directed mutagenesis, TPEN chelator controls\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro efflux assay with radionuclide + two fluorescent dyes + mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"31697912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of Tmem163 in MIN6 pancreatic β-cells increases intracellular zinc and total insulin content but impairs glucose-stimulated insulin secretion, establishing a role for TMEM163 in zinc-regulated insulin storage.\",\n      \"method\": \"siRNA knockdown in MIN6 cells, zinc measurement, insulin content and secretion assays, glucose uptake assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype, single lab, moderate evidence\",\n      \"pmids\": [\"31813547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMEM163 specifically modulates channel properties and pharmacology of ATP-gated P2X receptors (P2XRs); TMEM163 is required for full function of neuronal P2XRs and ATP-evoked pain-related behavior in vivo.\",\n      \"method\": \"Genome-wide ORF functional screen, electrophysiology, in vivo behavioral assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen plus electrophysiology plus in vivo behavioral validation, strong mechanistic evidence\",\n      \"pmids\": [\"32492420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM163 forms homodimers and heterodimerizes with ZNT1, ZNT2, ZNT3, and ZNT4; these heterodimers partially co-localize in cells and exhibit similar zinc efflux function as TMEM163 homodimers. Plasma membrane localization of TMEM163 is not markedly altered by ZNT co-expression.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, functional zinc flux assays (Fluozin-3 and Newport Green), cell surface biotinylation\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with functional assay and localization, single lab\",\n      \"pmids\": [\"36204728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Missense variants in TMEM163 cause hypomyelinating leukodystrophy; mutant proteins show significant impairment in zinc efflux in vitro. Expression of mutant TMEM163 in an oligodendroglial cell line reduces mRNA expression of key myelin genes, reduces branching, and increases cell death.\",\n      \"method\": \"In vitro zinc efflux assays with patient-derived mutant proteins, oligodendroglial cell line functional assays (branching, apoptosis, myelin gene expression), genomic sequencing\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional zinc efflux assay with disease variants plus cellular phenotype in relevant cell type\",\n      \"pmids\": [\"35953447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"De novo heterozygous variants L76R and L76P in TMEM163 cause hypomyelinating leukodystrophy; L76R attenuates and L76P enhances zinc efflux in HeLa cells. Knockdown of tmem163a/b in zebrafish causes myelin deficit, locomotor disability, and oligodendrocyte apoptosis; human wild-type TMEM163 rescues the phenotype while L76P and L76R mutants aggravate it.\",\n      \"method\": \"Zinc flux assays in stable HeLa cell lines, zebrafish morphant model with rescue experiments, whole exome sequencing\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional assay plus in vivo zebrafish model with rescue, multiple orthogonal methods\",\n      \"pmids\": [\"35455965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM163 functions as a vesicular Zn2+ transporter in a subset of dorsal root ganglion neurons; in aged mice, TMEM163 expression and vesicular Zn2+ are elevated, and excessive Zn2+ release from TMEM163+ primary afferents dampens NPY+ inhibitory interneuron activity, causing disinhibition of itch-transmitting circuits and chronic itch.\",\n      \"method\": \"In vivo mouse aging model, Zn2+ imaging, electrophysiology of spinal circuits, Zn2+ chelation in spinal dorsal horn, neuroanatomical tracing\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo functional model with circuit-level electrophysiology and pharmacological rescue, single study\",\n      \"pmids\": [\"39602426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZnT3 and TMEM163 physically interact (co-immunoprecipitation) and cooperatively promote zinc efflux in hippocampal neurons; under ischemic (OGD) conditions both proteins translocate from the plasma membrane to the cytoplasm, and their overexpression exacerbates extracellular zinc overload and neuronal apoptosis, while silencing attenuates zinc overload.\",\n      \"method\": \"Co-immunoprecipitation, cell surface biotinylation, siRNA silencing and plasmid overexpression, FluoZin-3 zinc imaging, TUNEL apoptosis assay, MTT viability assay\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus functional assays with KD/OE, single lab, moderate evidence\",\n      \"pmids\": [\"41504061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A conserved N-terminal acidic dileucine motif (LEDRGL69L70) in TMEM163 is essential for its interaction with AP-3 and BLOC-1 complexes but dispensable for binding AP-1, AP-2, and BLOC-2. Mutation of this motif causes TMEM163 accumulation at the plasma membrane. Loss of either BLOC-1 or AP-3 enhances TMEM163 binding to the other, suggesting competitive binding during sequential trafficking of TMEM163 to platelet dense granules.\",\n      \"method\": \"Co-immunoprecipitation, dileucine motif mutagenesis, confocal microscopy of subcellular localization, MEG-01 cell knockouts of endosomal trafficking complexes, proteasome inhibitor assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP with mutagenesis plus localization studies and multiple genetic backgrounds, single study with orthogonal methods\",\n      \"pmids\": [\"41985787\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM163 is a zinc efflux transporter (designated ZNT11) belonging to the cation diffusion facilitator (CDF)/SLC30 family that localizes to the plasma membrane, lysosomes, early endosomes, and synaptic vesicles; it functions as a proton-dependent, dimer-forming zinc effluxer whose conserved aspartate residues (D124/D128) and E286 are critical for transport activity, it physically interacts with TRPML1, ZNT1/2/3, and ZnT3 to modulate cellular zinc homeostasis, its trafficking to lysosome-related organelles is sequentially governed by AP-3 and BLOC-1 via a dileucine sorting motif, and it additionally modulates P2X receptor channel properties and synaptic zinc signaling relevant to pain and itch circuits.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TMEM163 is a proton-coupled zinc efflux transporter of the cation diffusion facilitator family that operates at the plasma membrane, synaptic vesicles, endosomes, and lysosome-related organelles to regulate cellular and vesicular zinc homeostasis. It forms homodimers and heterodimers with ZNT-family transporters (ZNT1–4), and conserved aspartate residues (D124/D128) and E286 are critical for zinc transport activity [PMID:27917477, PMID:31697912, PMID:36204728]. TMEM163 physically interacts with TRPML1 to modulate intracellular zinc levels and with P2X receptors to regulate ATP-gated channel properties relevant to pain signaling, and its trafficking to lysosome-related organelles depends on an N-terminal dileucine motif recognized sequentially by AP-3 and BLOC-1 [PMID:25130899, PMID:32492420, PMID:41985787]. Missense variants in TMEM163 cause hypomyelinating leukodystrophy through impaired zinc efflux and oligodendrocyte dysfunction, as demonstrated by patient-derived mutant analysis and zebrafish rescue experiments [PMID:35953447, PMID:35455965].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that TMEM163 (SV31) is an integral membrane protein of synaptic vesicles resolved its subcellular identity and positioned it as a candidate vesicular transporter or signaling component.\",\n      \"evidence\": \"Subcellular fractionation, immunocytochemistry, and immunoelectron microscopy in brain tissue and heterologous expression systems\",\n      \"pmids\": [\"17623043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No transport function demonstrated\", \"Ligand or substrate unknown\", \"No knockout or knockdown phenotype assessed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that TMEM163 selectively binds Zn²⁺ and Ni²⁺ — but not other divalent cations — identified it as a zinc-binding protein and implied a role in zinc homeostasis.\",\n      \"evidence\": \"Recombinant protein metal-binding assays, FluoZin-3 live-cell imaging, sucrose density gradient fractionation in PC12 cells\",\n      \"pmids\": [\"21668449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding demonstrated but active transport not yet shown\", \"Physiological relevance of Ni²⁺ binding unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying TRPML1 as a physical interactor revealed that TMEM163 operates within a protein network governing lysosomal/endosomal zinc flux, and TMEM163 knockdown increasing intracellular zinc provided the first loss-of-function evidence for zinc efflux activity.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, mass spectrometry, N-terminal deletion mutagenesis, fluorescent zinc assays in HEK-293 cells\",\n      \"pmids\": [\"25130899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direction and mechanism of transport not defined\", \"TRPML1 interaction domain on TRPML1 side not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reconstitution in proteoliposomes proved TMEM163 is a bona fide proton-coupled zinc transporter (Km ~44 µM), and nanodisc experiments established that dimerization enhances Zn²⁺ binding, placing it functionally within the CDF/SLC30 family.\",\n      \"evidence\": \"Cell-free synthesis, nanodisc reconstitution, native mass spectrometry, proteoliposome transport assay with FluoZin-1, site-directed mutagenesis\",\n      \"pmids\": [\"27917477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transport stoichiometry (Zn²⁺:H⁺) not determined\", \"No structural model at atomic resolution\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of D124, D128, and E286 as essential residues for zinc efflux in human cells, combined with the finding that TMEM163 knockdown in pancreatic β-cells dysregulates insulin storage, defined the molecular determinants of transport and a physiological role in insulin-secreting cells.\",\n      \"evidence\": \"Site-directed mutagenesis with radionuclide (⁶⁵Zn) and dual fluorescent dye efflux assays; siRNA knockdown in MIN6 cells with insulin content/secretion measurements\",\n      \"pmids\": [\"31697912\", \"31813547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo β-cell phenotype in knockout animals not assessed\", \"Whether E286K is a natural variant with clinical consequence was not established at this time\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A genome-wide functional screen uncovered TMEM163 as a modulator of P2X receptor channel properties, expanding its role beyond zinc transport to regulation of purinergic signaling and ATP-evoked pain behavior.\",\n      \"evidence\": \"Genome-wide ORF screen, electrophysiology, and in vivo behavioral pain assays in mice\",\n      \"pmids\": [\"32492420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of P2X modulation (direct binding vs. zinc-dependent) not resolved\", \"Which P2X subunit(s) are the primary physiological targets in vivo unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that TMEM163 heterodimerizes with ZNT1–4 established it as an integral member of the ZNT transporter network, and identification of causative missense variants in hypomyelinating leukodystrophy — validated by zebrafish rescue — linked TMEM163 loss-of-function to a human Mendelian disease affecting myelination.\",\n      \"evidence\": \"Co-IP and zinc flux assays for ZNT interactions; patient variant functional assays in HeLa and oligodendroglial lines; zebrafish morphant model with human mRNA rescue\",\n      \"pmids\": [\"36204728\", \"35953447\", \"35455965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for ZNT heterodimerization unknown\", \"Why oligodendrocytes are selectively vulnerable to TMEM163 mutations not explained\", \"Genotype–phenotype correlation across different leukodystrophy variants incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that TMEM163 loads vesicular zinc in DRG neurons and that age-related upregulation of TMEM163 causes excessive spinal zinc release and chronic itch via disinhibition of NPY⁺ interneurons established a circuit-level role for TMEM163-dependent zinc signaling in somatosensory pathology.\",\n      \"evidence\": \"In vivo mouse aging model, zinc imaging, spinal cord electrophysiology, zinc chelation rescue\",\n      \"pmids\": [\"39602426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal relationship tested only pharmacologically, not with conditional TMEM163 knockout\", \"Generalizability beyond aged-mouse itch model not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cooperative zinc efflux by ZnT3–TMEM163 complexes in hippocampal neurons, and their ischemia-induced internalization with consequent extracellular zinc overload, extended the functional relevance of TMEM163 heterodimers to excitotoxic neuronal injury.\",\n      \"evidence\": \"Co-IP, surface biotinylation, siRNA/overexpression, FluoZin-3 zinc imaging, TUNEL and MTT assays in oxygen-glucose deprivation model\",\n      \"pmids\": [\"41504061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ischemia-triggered internalization not determined\", \"In vivo stroke model validation lacking\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mapping the LEDRGL69L70 dileucine motif as the AP-3/BLOC-1 recognition site, and showing competitive sequential binding of these complexes, resolved the trafficking mechanism by which TMEM163 reaches lysosome-related organelles such as platelet dense granules.\",\n      \"evidence\": \"Dileucine mutagenesis, co-IP with AP and BLOC complexes, confocal localization, MEG-01 knockout lines\",\n      \"pmids\": [\"41985787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same sorting motif governs TMEM163 targeting in neurons not tested\", \"Structural basis of AP-3 vs. BLOC-1 competitive binding not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structure of TMEM163 exists, the Zn²⁺:H⁺ transport stoichiometry is undefined, the mechanism by which TMEM163 modulates P2X receptor gating (direct binding versus zinc-mediated) is unresolved, and the selective vulnerability of oligodendrocytes to TMEM163 mutations remains unexplained.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure\", \"Transport stoichiometry undetermined\", \"P2X modulation mechanism unresolved\", \"Oligodendrocyte-selective pathology mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [3, 4, 8, 9, 10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 7, 12]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [3, 4, 8, 9]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MCOLN1\",\n      \"SLC30A1\",\n      \"SLC30A2\",\n      \"SLC30A3\",\n      \"SLC30A4\",\n      \"P2RX\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}