{"gene":"ATP2C1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1989,"finding":"PMR1 (yeast ortholog of ATP2C1) encodes a P-type ATPase that functions as a Ca2+ pump affecting transit through the secretory pathway; loss of PMR1 causes defects in outer-chain glycosylation of secretory proteins and suppresses lethality of ypt1-1, placing PMR1 in the secretory pathway upstream of Golgi processing.","method":"Genetic epistasis (suppressor screen, ypt1-1 rescue), sequence comparison, functional phenotypic analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — foundational genetic epistasis paper, highly cited, replicated by subsequent work","pmids":["2526682"],"is_preprint":false},{"year":1992,"finding":"Yeast PMR1 localizes to a Golgi-like organelle (comigrates with Golgi markers in subcellular fractionation; punctate immunofluorescence pattern) and is required for normal Golgi function including proteolytic processing of pro-alpha factor and outer-chain glycosylation; defects are reversed by millimolar extracellular Ca2+, consistent with a Ca2+ pump role.","method":"Subcellular fractionation, indirect immunofluorescence, double-label co-localization, genetic epistasis with sec mutants, Ca2+ rescue experiments","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in a single highly-cited study, functionally linked localization","pmids":["1379856"],"is_preprint":false},{"year":1997,"finding":"PMR1 is a Ca2+-transporting ATPase in the yeast Golgi; biochemically demonstrated by ATP-dependent, protonophore-insensitive 45Ca2+ uptake in Golgi-enriched fractions; active-site Asp-371 mutation abolishes Ca2+ transport without disrupting Golgi targeting; inhibitor sensitivity (vanadate, thapsigargin, cyclopiazonic acid) and substrate affinity differ from SERCA and PMCA, defining a distinct P-type Ca2+-ATPase subgroup.","method":"In vitro Ca2+ transport assay (45Ca2+ uptake), active-site mutagenesis (Asp-371→Glu/Asn), sucrose gradient fractionation, inhibitor profiling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution-level in vitro Ca2+ transport assay combined with active-site mutagenesis","pmids":["9092527"],"is_preprint":false},{"year":1998,"finding":"The yeast Pmr1 (ATP2C1 ortholog) supplies the secretory pathway with both Ca2+ and Mn2+ required for N-linked and O-linked glycosylation (Mn2+-dependent) and accurate vacuolar sorting of carboxypeptidase Y (Ca2+-dependent); Pmr1 also supports ER-associated protein degradation of misfolded proteins.","method":"Genetic complementation (SERCA expression rescue), phenotypic analysis of pmr1 mutants, ion supplementation experiments","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genetic and biochemical approaches, replicated across labs","pmids":["9571246"],"is_preprint":false},{"year":1999,"finding":"PMR1 is the major regulator of ER Ca2+ levels in yeast; aequorin-based measurement showed ER lumen free Ca2+ is ~10 µM (far lower than mammalian ER), thapsigargin-insensitive, and reduced by ~50% in pmr1 null mutants, establishing PMR1/SPCA1 as a major contributor to ER Ca2+ sequestration.","method":"Organelle-targeted aequorin luminescence (direct measurement of ER lumenal free Ca2+) in pmr1 null mutants vs. wild-type","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — direct quantitative in-organello Ca2+ measurement with genetic KO","pmids":["10469652"],"is_preprint":false},{"year":1999,"finding":"An N-terminal EF hand-like motif in Pmr1 binds Ca2+ (demonstrated with recombinant bacterial fusions) and modulates ion transport; point mutations D51A and D53A reduce Ca2+ transport affinity; the double mutant blocks ER exit; in-frame deletions abolish function; mutations also alter relative affinity for Ca2+ vs. Mn2+, and perturb proteolytic stability of the ATP-binding domain.","method":"Recombinant protein Ca2+-binding assay, site-directed mutagenesis, 45Ca2+ transport assay, ER exit/trafficking analysis, proteolytic stability assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assay plus mutagenesis plus functional transport assays","pmids":["10545175"],"is_preprint":false},{"year":1999,"finding":"In the absence of Pmr1 (yeast ATP2C1 ortholog), compensatory calcineurin-dependent induction of the vacuolar Ca2+-ATPase Pmc1 occurs, together with increased H+/Ca2+ exchange activity, demonstrating that Pmr1 is the dominant Ca2+ pump under normal conditions and that loss of Pmr1 triggers a specific compensatory Ca2+ homeostasis response.","method":"Subcellular fractionation, Ca2+ transport activity assays, promoter-reporter assays, Western blotting, calcineurin inhibitor (FK506) treatment","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 — multiple complementary methods linking Pmr1 loss to compensatory Ca2+ transport induction","pmids":["10431803"],"is_preprint":false},{"year":2000,"finding":"Mutations in ATP2C1, encoding a Ca2+ pump that sequesters calcium into the Golgi, cause Hailey-Hailey disease; cytoplasmic Ca2+ regulation is impaired in cultured keratinocytes from HHD patients, and the epidermal Ca2+ gradient is attenuated in vivo.","method":"Positional cloning, mutation identification in 21 kindreds, cytoplasmic Ca2+ measurements in cultured keratinocytes, in vivo Ca2+ gradient measurement","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — foundational disease-gene paper with functional Ca2+ measurements, independently replicated","pmids":["10615129"],"is_preprint":false},{"year":2000,"finding":"Transmembrane segment M6 residue Asp778 is essential for cation binding and transport by Pmr1; D778A abolishes Ca2+- and Mn2+-dependent ATP hydrolysis and phosphoenzyme formation from ATP, while reverse phosphorylation from Pi is preserved but insensitive to Ca2+ or Mn2+. Residue Gln783 in M6 is critical for Mn2+ selectivity; Q783A retains Ca2+-ATPase activity (Km ~0.06 µM) but Mn2+-ATPase is nearly abolished even at 10 µM Mn2+.","method":"Purified histidine-tagged Pmr1, in vitro ATPase assay, phosphoenzyme intermediate assay (forward from ATP and reverse from Pi), site-directed mutagenesis, molecular modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — purified protein, reconstituted enzymatic assays, mutagenesis with mechanistic resolution","pmids":["10801856"],"is_preprint":false},{"year":2000,"finding":"Phenotypic screen of 35 transmembrane-domain mutations in Pmr1 identified residues in M4, M5, M6, M7, M8 critical for Ca2+ and/or Mn2+ transport; Class 2 (loss-of-function) mutants lacked 45Ca2+ transport; notably Asn774 and Asp778 in M6 are essential; Class 3 mutants (e.g., Q783A) show selective loss of Mn2+ transport, indicating differential ion selectivity determinants.","method":"Systematic mutagenesis, phenotypic growth assays (BAPTA and Mn2+ toxicity), 45Ca2+ transport assay, Golgi localization analysis, protein conformation assessment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis combined with functional transport assays","pmids":["10801855"],"is_preprint":false},{"year":2000,"finding":"C. elegans PMR1 (ATP2C1 ortholog) transports Ca2+ and Mn2+ with high affinity into the Golgi apparatus in a thapsigargin-insensitive manner when ectopically expressed in COS-1 cells; accumulated Ca2+ is releasable by IP3, establishing the Golgi as an IP3-sensitive Ca2+ store.","method":"Ectopic expression in permeabilized COS-1 cells, direct ion transport assay, IP3-triggered Ca2+ release measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct functional reconstitution of Ca2+ and Mn2+ transport in heterologous cells","pmids":["11134055"],"is_preprint":false},{"year":2003,"finding":"Human ATP2C1 (SPCA1) protein (~115 kDa) localizes to the Golgi apparatus in human keratinocytes; HHD keratinocytes with decreased SPCA1 protein show slower Golgi Ca2+ refill and significantly lower maximal intraorganelle Ca2+ concentration, measured with Golgi-targeted aequorin.","method":"Western blotting, immunofluorescence localization, organelle-targeted aequorin Ca2+ measurement in intact keratinocytes and in vivo","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — direct Golgi Ca2+ measurement using aequorin, localization confirmed, with disease-relevant functional consequence","pmids":["14632183"],"is_preprint":false},{"year":2003,"finding":"SPCA1 (ATP2C1) is responsible for Ca2+ uptake in a subfraction of the Golgi in HeLa cells; RNAi knockdown of SPCA1 reduced Golgi lumenal Ca2+ as measured by Golgi-targeted aequorin; absence of SPCA1 reduced frequency of baseline Ca2+ oscillations but did not abolish them, indicating partial contribution to cytosolic Ca2+ signaling.","method":"RNA interference, Golgi-targeted aequorin Ca2+ measurement, cytosolic Ca2+ imaging","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — RNAi knockdown with direct organellar Ca2+ measurement","pmids":["12804581"],"is_preprint":false},{"year":2003,"finding":"Packing interaction between Val335 in M4 and Gln783 in M6 of PMR1 is critical for Mn2+ transport selectivity; V335G mimics the Mn2+-selective defect of Q783A and V335I suppresses it; exchange of side chains at 335 and 783 produces ion selectivity defects, suggesting this region constitutes a conformation-sensitive gate for Mn2+ access.","method":"Scanning mutagenesis, cation-dependent ATPase assay with purified enzyme, phenotypic growth assays, homology modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — purified enzyme assays combined with systematic mutagenesis and suppressor analysis","pmids":["12824173"],"is_preprint":false},{"year":2004,"finding":"ATP2C1/SPCA1 knockdown (siRNA) in pancreatic beta-cells reduces Ca2+ uptake into the ER and secretory vesicles by ~20% (measured with organelle-targeted aequorins), enhances L-type Ca2+ channel flux, and augments glucose-stimulated insulin secretion, demonstrating a functional role in beta-cell Ca2+ homeostasis and insulin secretion.","method":"siRNA knockdown, organelle-targeted aequorin Ca2+ measurement in permeabilized cells, intact cell Ca2+ imaging (fluo-3), insulin secretion assay, subcellular fractionation","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — siRNA KD with direct organellar Ca2+ measurement and defined physiological output","pmids":["14747290"],"is_preprint":false},{"year":2004,"finding":"ATP2C1 deficiency (siRNA knockdown) impairs post-translational glycoprotein processing (wild-type thyroglobulin) and ER-associated degradation of misfolded thyroglobulin via the secretory pathway, while rendering cells hypersensitive to ER stress without constitutively activating the UPR (PERK, ATF6, or Ire1/XBP1 pathways unaffected).","method":"siRNA knockdown, metabolic labeling and pulse-chase for glycoprotein processing, ER stress induction and UPR pathway monitoring","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KD with multiple defined functional readouts in secretory pathway processing","pmids":["15623514"],"is_preprint":false},{"year":2006,"finding":"Yeast Pmr1 functions upstream of Npr1 and Gln3 in opposition to Lst8 in TOR signaling; pmr1 deletion confers rapamycin resistance; Ca2+/Mn2+ ion homeostasis controlled by Pmr1 is required for normal TOR pathway signaling including nuclear translocation of Gln3 and Gap1 permease regulation.","method":"Genome-wide deletion screen for rapamycin resistance, epistasis analysis (double mutants), Gln3 reporter assays, plasma membrane permease localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established, but indirect link between Ca2+/Mn2+ and TOR requires further mechanistic resolution","pmids":["17095607"],"is_preprint":false},{"year":2007,"finding":"Homozygous knockout of Atp2c1 in mice causes embryonic lethality by E10.5 with dilated Golgi membranes, fewer stacked leaflets, expanded Golgi amount, increased Golgi-associated vesicles, increased apoptosis, and large cytoplasmic lipid accumulation, demonstrating that SPCA1 is essential for Golgi structural integrity and lipid handling.","method":"Targeted gene knockout in mice, embryo histology, electron microscopy of Golgi ultrastructure, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with detailed ultrastructural and cell biological phenotyping","pmids":["17597066"],"is_preprint":false},{"year":2009,"finding":"SPCA1 (ATP2C1) localizes to the juxtanuclear Golgi in N2a neuroblastoma cells; SPCA1 knockdown by RNAi impairs Golgi Ca2+ homeostasis, delays neuronal differentiation (increased neurite number, reduced length), and disrupts protein trafficking including Golgi-localized and plasma membrane-targeted constructs; in hippocampal neurons, SPCA1 is differentially distributed in Golgi stacks depending on differentiation stage.","method":"RNAi knockdown, Ca2+ imaging (Golgi-targeted cameleon), live imaging of trafficking markers, immunocytochemistry, primary neuron culture","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — RNAi KD with direct Golgi Ca2+ measurement, trafficking assays, and defined differentiation phenotype","pmids":["19793975"],"is_preprint":false},{"year":2010,"finding":"SPCA1 (ATP2C1) inhibition in MDA-MB-231 basal-like breast cancer cells alters calcium-dependent proprotein convertase activity in the secretory pathway, causing defective processing of pro-IGF1R to functional IGF1Rβ and accumulation of inactive trans-Golgi network pro-IGF1R, without global alterations in cytosolic Ca2+ signaling.","method":"SPCA1 inhibition, 3D culture morphology assay, Western blotting for IGF1R processing intermediates, Ca2+ imaging","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological inhibition with defined substrate processing readout; no genetic rescue","pmids":["20837466"],"is_preprint":false},{"year":2010,"finding":"SPCA1 is located predominantly on lateral rims of Golgi cisternae, tubular non-compact zones interconnecting Golgi stacks, and tubular TGN regions (not the core of cisternae); SPCA1 knockdown causes Golgi fragmentation (loss of cis-most and trans-most cisternae), inhibits exit of VSV-G from the Golgi, and delays retrograde redistribution of glycosylation enzymes by brefeldin A, establishing SPCA1 as essential for intra-Golgi transport and ribbon maintenance.","method":"Immunoelectron microscopy for precise Golgi localization, RNAi knockdown, VSV-G trafficking assay, brefeldin A redistribution assay","journal":"Traffic","confidence":"High","confidence_rationale":"Tier 2 — precise ultrastructural localization combined with RNAi and multiple trafficking readouts","pmids":["20604898"],"is_preprint":false},{"year":2013,"finding":"PMR-1 (C. elegans ortholog of ATP2C1/SPCA1) plays an essential role in embryonic cell migration; pmr-1 mutants show reduced migration rates of ventral neuroblasts and other blastomeres; genetic interaction with itr-1/IP3R and unc-68/RyR (Ca2+ channels) modulates embryonic lethality, placing pmr-1 in a Ca2+ homeostasis network that regulates cytoskeletal dynamics during gastrulation.","method":"Genetic screens, live imaging of cell migration, gene interaction (double mutant) analysis with IP3R and RyR","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — epistasis plus live imaging with quantified migration rates","pmids":["23696750"],"is_preprint":false},{"year":2014,"finding":"Cofilin-1 (CFL-1) recruits F-actin to the phosphorylation domain (P-domain) of SPCA1 at the TGN; a 132-aa portion of the SPCA1 P-domain interacts with actin in a CFL-1-dependent manner; mutagenesis of the CFL-1-binding site in SPCA1 impairs Ca2+ entry into the TGN and secretory cargo sorting; expression of the P-domain in HeLa cells acts as a dominant-negative for TGN Ca2+ import and cargo sorting.","method":"Purified protein interaction assay, F-actin co-sedimentation with Ni-NTA agarose beads, site-directed mutagenesis, dominant-negative expression in HeLa cells, TGN Ca2+ measurement, cargo sorting assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — purified protein interaction assay combined with mutagenesis and functional cellular readouts","pmids":["25179631"],"is_preprint":false},{"year":2017,"finding":"SPCA1 (ATP2C1) calcium transport activity is required for maturation of diverse viral glycoproteins (measles, dengue, West Nile, Zika, chikungunya); SPCA1-deficient cells fail to proteolytically mature viral glycoproteins via trans-Golgi network proteases that require Ca2+ for activity, preventing viral spread.","method":"Genome-wide haploid cell knockout screen, genetic KO validation, viral spread assays, glycoprotein maturation Western blotting","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen plus clean KO with defined biochemical mechanism (Ca2+-dependent protease activity)","pmids":["29024641"],"is_preprint":false},{"year":2018,"finding":"SPCA1 activity at the TGN is controlled by sphingomyelin content; local sphingomyelin synthesis promotes Ca2+ flux into TGN lumen via SPCA1; SPCA1-driven Ca2+ release enables Ca2+-binding protein Cab45 to oligomerize and package specific secreted proteins into sphingomyelin-enriched vesicular carriers, coupling sphingomyelin synthesis to secretory protein sorting.","method":"Genetic perturbation of sphingomyelin synthesis, Ca2+ imaging at TGN, Cab45 oligomerization assay, vesicle isolation and cargo analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods linking SPCA1 Ca2+ transport to lipid synthesis and cargo sorting","pmids":["30393074"],"is_preprint":false},{"year":2018,"finding":"Loss of Spca1 in mouse neuroepithelial cells causes failure of apical constriction (not cell death), associated with disrupted myosin II localization, impaired actin dynamics, and mislocalization of cofilin-1, leading to cranial exencephaly and spinal cord defects during neural tube closure.","method":"Novel Spca1 mouse allele (KO), live imaging of neuroepithelial cell shape, myosin II and cofilin-1 immunofluorescence localization, actin dynamics analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with mechanistic dissection of cytoskeletal effectors","pmids":["30228103"],"is_preprint":false},{"year":2018,"finding":"SPCA1 overexpression induces store-independent Ca2+ entry (SICE) via functional coupling with Orai1 at the plasma membrane (TIRF co-localization), independently of STIM1; this elevates cytosolic and non-ER store Ca2+ and induces Golgi swelling with TFE3 nuclear translocation (Golgi stress marker); HHD-associated SPCA1 mutations impair Ca2+ transport, Orai1 activation, or both.","method":"SPCA1 overexpression, Orai1 RNAi knockdown, TIRF microscopy co-localization, cytosolic Ca2+ and non-ER store Ca2+ measurement, Golgi morphology analysis, TFE3 translocation assay, functional analysis of HHD mutations","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 — overexpression and KD with multiple readouts; interaction mechanism not reconstituted in vitro","pmids":["29555205"],"is_preprint":false},{"year":2019,"finding":"The N-terminal EF-hand-like motif of SPCA1a (absent in SPCA2) binds Ca2+ and regulates pump activity; mutation of this motif lowers Ca2+ turnover rate relative to Mn2+, increases substrate affinity, and reduces biphasic activation of SPCA1a; Ca2+ binding to this motif promotes SPCA1a autophosphorylation, especially relevant at high Ca2+ load or low ATP.","method":"Purified recombinant SPCA1a and SPCA2 from yeast expression system, in vitro ATPase assay, autophosphorylation assay, Ca2+-binding assay, mutagenesis of EF-hand motif","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — purified protein biochemistry with mutagenesis and multiple functional assays","pmids":["30923126"],"is_preprint":false},{"year":2019,"finding":"TMEM165 stability and Golgi localization is directly dependent on SPCA1 Mn2+-pumping activity; SPCA1-deficient cells show constitutive lysosomal degradation of TMEM165; only SPCA1 mutant Q747A (favoring Mn2+ pumping) rescues TMEM165 abundance, establishing that SPCA1-mediated Mn2+ transport into the Golgi is necessary to maintain TMEM165.","method":"SPCA1 KO (Hap1 cells), SPCA1 mutant complementation, TMEM165 localization by immunofluorescence, lysosomal degradation assay, SERCA2b overexpression rescue","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 — clean KO with mechanistic rescue using transport-selective mutants","pmids":["31652305"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of human SPCA1 (hSPCA1) in six intermediate states reveal a near-complete Ca2+ transport conformational cycle; hSPCA1 undergoes unique conformational changes during ATP binding and phosphorylation compared to other P-type II ATPases; separation of transmembrane helices 4L and 6 causes Ca2+-binding site distortion enabling a distinct Ca2+ release mechanism; the CaE2P state of P-type IIA ATPases was directly visualized.","method":"Cryo-electron microscopy (6 structures at multiple states), molecular dynamics simulations, structural analysis of transmembrane helix movements","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 — multiple cryo-EM structures resolving the conformational cycle with MD simulation validation","pmids":["37258749"],"is_preprint":false}],"current_model":"ATP2C1 encodes SPCA1, a P-type Ca2+/Mn2+-ATPase that localizes to the Golgi apparatus (especially the trans-Golgi network lateral rims and TGN tubules), where it uses ATP hydrolysis via a phosphoenzyme intermediate to actively pump cytosolic Ca2+ and Mn2+ into the Golgi lumen; Ca2+ transport is modulated by an N-terminal EF-hand-like motif that binds Ca2+ to promote autophosphorylation, and by cofilin-1-dependent recruitment of F-actin to the P-domain; Golgi lumenal Ca2+ supplied by SPCA1 drives Ca2+-dependent protein processing (glycosylation, proprotein convertase activity, viral glycoprotein maturation), Cab45-mediated oligomerization and selective secretory cargo sorting into sphingomyelin-enriched TGN vesicles, and cytoskeletal contractility (via myosin II and cofilin-1) required for neural tube closure; loss of one functional copy causes Hailey-Hailey disease through haploinsufficiency-driven impairment of cytoplasmic Ca2+ regulation in keratinocytes, while complete loss causes embryonic lethality associated with Golgi structural disruption and increased apoptosis."},"narrative":{"teleology":[{"year":1989,"claim":"Identification of PMR1 as the founding member of a distinct P-type ATPase subfamily acting in the secretory pathway established that an active Ca²⁺ pump is required upstream of Golgi-dependent processing events.","evidence":"Genetic suppressor screen (ypt1-1 rescue) and sequence analysis in S. cerevisiae","pmids":["2526682"],"confidence":"High","gaps":["Subcellular localization not yet determined","Ion specificity (Ca²⁺ vs. Mn²⁺) not resolved","No mammalian ortholog yet identified"]},{"year":1992,"claim":"Direct localization of PMR1 to a Golgi-like compartment linked its Ca²⁺-pumping function to Golgi-dependent proteolytic processing and glycosylation.","evidence":"Subcellular fractionation, immunofluorescence co-localization with Golgi markers, and phenotypic rescue by extracellular Ca²⁺ in yeast","pmids":["1379856"],"confidence":"High","gaps":["Transport activity not directly measured","Whether PMR1 also transports Mn²⁺ not tested"]},{"year":1997,"claim":"Reconstitution of ATP-dependent ⁴⁵Ca²⁺ transport and demonstration that active-site Asp371 is required for catalysis established PMR1 as a bona fide Ca²⁺-transporting ATPase biochemically distinct from SERCA and PMCA.","evidence":"In vitro ⁴⁵Ca²⁺ uptake in Golgi-enriched fractions, active-site mutagenesis, and inhibitor profiling in yeast","pmids":["9092527"],"confidence":"High","gaps":["Mn²⁺ transport not biochemically demonstrated","No structural information"]},{"year":1998,"claim":"Demonstration that PMR1 supplies both Ca²⁺ and Mn²⁺ to the secretory pathway expanded its role beyond Ca²⁺ homeostasis to include Mn²⁺-dependent glycosylation and protein quality control.","evidence":"Genetic complementation with SERCA, ion supplementation rescue of pmr1Δ glycosylation and sorting defects","pmids":["9571246"],"confidence":"High","gaps":["Relative contributions of Ca²⁺ vs. Mn²⁺ to individual downstream processes not separated","Mammalian dual-ion transport not yet shown"]},{"year":1999,"claim":"Quantitative measurement of ER/Golgi lumenal Ca²⁺ and identification of an N-terminal EF-hand-like regulatory motif revealed that PMR1 is the dominant Ca²⁺ pump maintaining secretory pathway stores and that its activity is autoregulated by Ca²⁺ binding.","evidence":"Organelle-targeted aequorin in pmr1Δ yeast (PMID:10469652); recombinant Ca²⁺-binding assays and mutagenesis of the EF-hand motif (PMID:10545175); compensatory induction of vacuolar pumps upon PMR1 loss (PMID:10431803)","pmids":["10469652","10545175","10431803"],"confidence":"High","gaps":["Whether the EF-hand motif functions identically in the mammalian ortholog","Structural basis of EF-hand regulation unknown"]},{"year":2000,"claim":"Positional cloning of ATP2C1 mutations in Hailey-Hailey disease families, combined with demonstration of impaired keratinocyte Ca²⁺ regulation, established haploinsufficiency of the human Golgi Ca²⁺ pump as the cause of this genodermatosis.","evidence":"Mutation identification in 21 HHD kindreds, cytoplasmic Ca²⁺ measurements in patient keratinocytes, in vivo epidermal Ca²⁺ gradient measurement","pmids":["10615129"],"confidence":"High","gaps":["Molecular mechanism linking Golgi Ca²⁺ deficit to keratinocyte adhesion failure not resolved","Genotype-phenotype correlations not established"]},{"year":2000,"claim":"Systematic mutagenesis of transmembrane helices identified Asp778 as essential for both Ca²⁺ and Mn²⁺ transport and Gln783 as a selective determinant of Mn²⁺ binding, defining the ion selectivity filter of the SPCA family.","evidence":"Purified Pmr1 ATPase and phosphoenzyme assays with D778A and Q783A mutants (PMID:10801856); phenotypic screen of 35 TM mutations with ⁴⁵Ca²⁺ transport (PMID:10801855); C. elegans PMR1 reconstitution in COS-1 cells confirming dual Ca²⁺/Mn²⁺ transport (PMID:11134055)","pmids":["10801856","10801855","11134055"],"confidence":"High","gaps":["No high-resolution structure of the ion-binding site","How Gln783–Val335 packing controls gating only partially resolved"]},{"year":2003,"claim":"Direct Golgi-targeted aequorin measurements in human keratinocytes and HeLa cells confirmed that SPCA1 is the principal Ca²⁺ pump maintaining Golgi lumenal Ca²⁺ stores in mammalian cells, and that HHD patient cells have reduced Golgi Ca²⁺.","evidence":"Golgi-targeted aequorin in HHD vs. control keratinocytes (PMID:14632183); SPCA1 RNAi in HeLa with Golgi Ca²⁺ readout (PMID:12804581)","pmids":["14632183","12804581"],"confidence":"High","gaps":["Relative contribution of SPCA1 vs. SERCA to Golgi Ca²⁺ filling not fully quantified","Packing interaction between V335 and Q783 only confirmed with yeast enzyme (PMID:12824173)"]},{"year":2004,"claim":"SPCA1 knockdown impaired glycoprotein processing, ER-associated degradation, and insulin secretion, demonstrating that SPCA1-supplied Golgi Ca²⁺/Mn²⁺ is broadly required for secretory pathway quality control and regulated exocytosis.","evidence":"siRNA in pancreatic beta-cells with organelle-targeted aequorin and insulin secretion assay (PMID:14747290); siRNA in thyroid cells with pulse-chase glycoprotein processing and UPR monitoring (PMID:15623514)","pmids":["14747290","15623514"],"confidence":"High","gaps":["Whether Ca²⁺ or Mn²⁺ depletion is the primary driver of each phenotype not separated","Beta-cell phenotype not confirmed in genetic KO models"]},{"year":2010,"claim":"Immuno-EM revealed SPCA1 concentrates on lateral rims and tubular non-compact zones of the Golgi, and its loss causes Golgi fragmentation, blocked anterograde/retrograde transport, and defective proprotein convertase-dependent processing of IGF1R.","evidence":"Immunoelectron microscopy localization, RNAi with VSV-G and BFA trafficking assays (PMID:20604898); SPCA1 inhibition with IGF1R processing readout in breast cancer cells (PMID:20837466)","pmids":["20604898","20837466"],"confidence":"High","gaps":["What retains SPCA1 at lateral rims vs. cisternal cores unknown","IGF1R processing result based on pharmacological inhibition without genetic rescue"]},{"year":2014,"claim":"Discovery that cofilin-1 recruits F-actin to the SPCA1 P-domain to regulate TGN Ca²⁺ import and cargo sorting revealed an unexpected cytoskeletal–ion pump coupling mechanism at the TGN.","evidence":"Purified protein interaction assay, F-actin co-sedimentation, mutagenesis of CFL1-binding site, dominant-negative P-domain expression in HeLa cells","pmids":["25179631"],"confidence":"High","gaps":["Structural basis of actin–P-domain interaction unknown","Whether cofilin-1 modulates Mn²⁺ transport not tested"]},{"year":2017,"claim":"Genome-wide screens identified SPCA1 as essential for maturation of diverse viral glycoproteins, establishing Golgi Ca²⁺-dependent protease activity as a host dependency factor exploited by multiple enveloped viruses.","evidence":"Haploid cell KO screen, genetic KO validation, viral spread assays and glycoprotein maturation blots for measles, dengue, Zika, chikungunya, West Nile","pmids":["29024641"],"confidence":"High","gaps":["Specific Ca²⁺-dependent proteases responsible not identified for all viruses","In vivo relevance for viral pathogenesis not tested"]},{"year":2018,"claim":"SPCA1 was placed at the nexus of sphingomyelin-dependent Ca²⁺ signaling and selective secretory sorting: local SM synthesis activates SPCA1-mediated Ca²⁺ flux, enabling Cab45 oligomerization and cargo packaging, while in neuroepithelium SPCA1 loss disrupts myosin II and cofilin-1 localization causing neural tube closure failure.","evidence":"SM synthesis perturbation with TGN Ca²⁺ imaging and Cab45 oligomerization assay (PMID:30393074); Spca1 KO mouse with live imaging of neuroepithelial cell shape and cytoskeletal localization (PMID:30228103)","pmids":["30393074","30228103"],"confidence":"High","gaps":["How SM content modulates SPCA1 activity (direct lipid–protein interaction vs. membrane property) not resolved","Whether neural tube defect is Ca²⁺- or Mn²⁺-dependent not distinguished"]},{"year":2019,"claim":"Purified SPCA1a biochemistry confirmed the N-terminal EF-hand promotes autophosphorylation and tunes Ca²⁺/Mn²⁺ selectivity, while SPCA1-dependent Mn²⁺ delivery to the Golgi was shown to be specifically required for TMEM165 stability.","evidence":"Purified recombinant SPCA1a ATPase/autophosphorylation assays with EF-hand mutants (PMID:30923126); SPCA1 KO Hap1 cells rescued by Mn²⁺-selective mutant Q747A restoring TMEM165 (PMID:31652305)","pmids":["30923126","31652305"],"confidence":"High","gaps":["Whether EF-hand regulation operates in vivo at physiological Ca²⁺ concentrations not confirmed","How Mn²⁺ depletion triggers TMEM165 lysosomal degradation mechanistically unclear"]},{"year":2023,"claim":"Cryo-EM structures of human SPCA1 across six transport intermediates revealed a near-complete conformational cycle, identifying unique TM4L–TM6 separation as the mechanism for Ca²⁺ release and directly visualizing the CaE2P state for the first time in a P-type IIA ATPase.","evidence":"Cryo-EM at multiple conformational states with molecular dynamics simulations","pmids":["37258749"],"confidence":"High","gaps":["No structure with Mn²⁺ bound; Mn²⁺ transport mechanism not structurally resolved","EF-hand domain not resolved in structures","Lipid interactions at the TM domain not captured"]},{"year":null,"claim":"How SPCA1-mediated Golgi Ca²⁺/Mn²⁺ supply is differentially decoded by downstream effectors in distinct cell types, and the structural basis for sphingomyelin- and cofilin-1-dependent regulation of SPCA1 activity, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of SPCA1 with Mn²⁺ bound or with the EF-hand domain resolved","Mechanism by which sphingomyelin modulates SPCA1 (direct vs. indirect) unknown","How Golgi Ca²⁺ deficit specifically impairs keratinocyte adhesion in HHD not molecularly defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[2,8,27,29]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2,3,10,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[27]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,11,12,18,20,29]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,10,11,14]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[20,22,24]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,15,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,23]}],"complexes":[],"partners":["CFL1","ORAI1","TMEM165","CAB45"],"other_free_text":[]},"mechanistic_narrative":"ATP2C1 encodes SPCA1, a P-type Ca²⁺/Mn²⁺-ATPase that localizes to the lateral rims and tubular regions of the Golgi apparatus, where it uses ATP hydrolysis via a phosphoenzyme intermediate to actively transport cytosolic Ca²⁺ and Mn²⁺ into the Golgi lumen, thereby maintaining Golgi ion homeostasis essential for protein glycosylation, proprotein convertase-dependent processing, secretory cargo sorting, and Golgi ribbon integrity [PMID:9092527, PMID:20604898, PMID:30393074, PMID:30923126]. Golgi lumenal Ca²⁺ supplied by SPCA1 drives Cab45-mediated oligomerization for selective cargo packaging into sphingomyelin-enriched TGN vesicles, supports Ca²⁺-dependent maturation of viral glycoproteins, and regulates cytoskeletal contractility through cofilin-1 and myosin II during neural tube closure [PMID:30393074, PMID:29024641, PMID:25179631, PMID:30228103]. An N-terminal EF-hand-like motif binds Ca²⁺ to promote autophosphorylation and modulate transport kinetics, while transmembrane residues Asp778 and Gln783 are critical determinants of Ca²⁺ versus Mn²⁺ selectivity [PMID:30923126, PMID:10801856, PMID:12824173]. Loss-of-function mutations in one copy of ATP2C1 cause Hailey-Hailey disease through haploinsufficiency-driven impairment of Ca²⁺ homeostasis in keratinocytes, while homozygous loss causes embryonic lethality with Golgi structural disruption [PMID:10615129, PMID:17597066]."},"prefetch_data":{"uniprot":{"accession":"P98194","full_name":"Calcium-transporting ATPase type 2C member 1","aliases":["ATP-dependent Ca(2+) pump PMR1","Ca(2+)/Mn(2+)-ATPase 2C1","Secretory pathway Ca(2+)-transporting ATPase type 1","SPCA1"],"length_aa":919,"mass_kda":100.6,"function":"ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both essential cofactors for processing and trafficking of newly synthesized proteins in the secretory pathway (PubMed:12707275, PubMed:16192278, PubMed:20439740, PubMed:21187401, PubMed:30923126). Within a catalytic cycle, acquires Ca(2+) or Mn(2+) ions on the cytoplasmic side of the membrane and delivers them to the lumenal side. The transfer of ions across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing to outward-facing state (PubMed:16192278, PubMed:16332677, PubMed:30923126). Plays a primary role in the maintenance of Ca(2+) homeostasis in the trans-Golgi compartment with a functional impact on Golgi and post-Golgi protein sorting as well as a structural impact on cisternae morphology (PubMed:14632183, PubMed:20439740). Responsible for loading the Golgi stores with Ca(2+) ions in keratinocytes, contributing to keratinocyte differentiation and epidermis integrity (PubMed:10615129, PubMed:14632183, PubMed:20439740). Participates in Ca(2+) and Mn(2+) ions uptake into the Golgi store of hippocampal neurons and regulates protein trafficking required for neural polarity (By similarity). May also play a role in the maintenance of Ca(2+) and Mn(2+) homeostasis and signaling in the cytosol while preventing cytotoxicity (PubMed:21187401)","subcellular_location":"Golgi apparatus, trans-Golgi network membrane; Golgi apparatus, Golgi stack membrane","url":"https://www.uniprot.org/uniprotkb/P98194/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP2C1","classification":"Not Classified","n_dependent_lines":103,"n_total_lines":1208,"dependency_fraction":0.08526490066225166},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GORASP2","stoichiometry":0.2},{"gene":"TMED10","stoichiometry":0.2},{"gene":"YIPF5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATP2C1","total_profiled":1310},"omim":[{"mim_id":"620693","title":"ASTEROID HOMOLOG 1; ASTE1","url":"https://www.omim.org/entry/620693"},{"mim_id":"613082","title":"ATPase, Ca(2+)-TRANSPORTING, TYPE 2C, MEMBER 2; ATP2C2","url":"https://www.omim.org/entry/613082"},{"mim_id":"606805","title":"GOLGI INTEGRAL MEMBRANE PROTEIN 4; GOLIM4","url":"https://www.omim.org/entry/606805"},{"mim_id":"604384","title":"ATPase, Ca(2+)-TRANSPORTING, TYPE 2C, MEMBER 1; ATP2C1","url":"https://www.omim.org/entry/604384"},{"mim_id":"169600","title":"HAILEY-HAILEY DISEASE; HHD","url":"https://www.omim.org/entry/169600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATP2C1"},"hgnc":{"alias_symbol":["KIAA1347","ATP2C1A","PMR1","SPCA1"],"prev_symbol":["BCPM"]},"alphafold":{"accession":"P98194","domains":[{"cath_id":"2.70.150.10","chopping":"2-251","consensus_level":"medium","plddt":76.2227,"start":2,"end":251},{"cath_id":"1.20.1110.10","chopping":"300-313_701-911","consensus_level":"high","plddt":86.0042,"start":300,"end":911},{"cath_id":"3.40.50.1000","chopping":"332-357_549-681","consensus_level":"medium","plddt":87.4577,"start":332,"end":681},{"cath_id":"3.40.1110.10","chopping":"364-543","consensus_level":"high","plddt":90.505,"start":364,"end":543}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P98194","model_url":"https://alphafold.ebi.ac.uk/files/AF-P98194-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P98194-F1-predicted_aligned_error_v6.png","plddt_mean":83.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP2C1","jax_strain_url":"https://www.jax.org/strain/search?query=ATP2C1"},"sequence":{"accession":"P98194","fasta_url":"https://rest.uniprot.org/uniprotkb/P98194.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P98194/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P98194"}},"corpus_meta":[{"pmid":"2526682","id":"PMC_2526682","title":"The 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functions as a Ca2+ pump affecting transit through the secretory pathway; loss of PMR1 causes defects in outer-chain glycosylation of secretory proteins and suppresses lethality of ypt1-1, placing PMR1 in the secretory pathway upstream of Golgi processing.\",\n      \"method\": \"Genetic epistasis (suppressor screen, ypt1-1 rescue), sequence comparison, functional phenotypic analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational genetic epistasis paper, highly cited, replicated by subsequent work\",\n      \"pmids\": [\"2526682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Yeast PMR1 localizes to a Golgi-like organelle (comigrates with Golgi markers in subcellular fractionation; punctate immunofluorescence pattern) and is required for normal Golgi function including proteolytic processing of pro-alpha factor and outer-chain glycosylation; defects are reversed by millimolar extracellular Ca2+, consistent with a Ca2+ pump role.\",\n      \"method\": \"Subcellular fractionation, indirect immunofluorescence, double-label co-localization, genetic epistasis with sec mutants, Ca2+ rescue experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single highly-cited study, functionally linked localization\",\n      \"pmids\": [\"1379856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PMR1 is a Ca2+-transporting ATPase in the yeast Golgi; biochemically demonstrated by ATP-dependent, protonophore-insensitive 45Ca2+ uptake in Golgi-enriched fractions; active-site Asp-371 mutation abolishes Ca2+ transport without disrupting Golgi targeting; inhibitor sensitivity (vanadate, thapsigargin, cyclopiazonic acid) and substrate affinity differ from SERCA and PMCA, defining a distinct P-type Ca2+-ATPase subgroup.\",\n      \"method\": \"In vitro Ca2+ transport assay (45Ca2+ uptake), active-site mutagenesis (Asp-371→Glu/Asn), sucrose gradient fractionation, inhibitor profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution-level in vitro Ca2+ transport assay combined with active-site mutagenesis\",\n      \"pmids\": [\"9092527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The yeast Pmr1 (ATP2C1 ortholog) supplies the secretory pathway with both Ca2+ and Mn2+ required for N-linked and O-linked glycosylation (Mn2+-dependent) and accurate vacuolar sorting of carboxypeptidase Y (Ca2+-dependent); Pmr1 also supports ER-associated protein degradation of misfolded proteins.\",\n      \"method\": \"Genetic complementation (SERCA expression rescue), phenotypic analysis of pmr1 mutants, ion supplementation experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genetic and biochemical approaches, replicated across labs\",\n      \"pmids\": [\"9571246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PMR1 is the major regulator of ER Ca2+ levels in yeast; aequorin-based measurement showed ER lumen free Ca2+ is ~10 µM (far lower than mammalian ER), thapsigargin-insensitive, and reduced by ~50% in pmr1 null mutants, establishing PMR1/SPCA1 as a major contributor to ER Ca2+ sequestration.\",\n      \"method\": \"Organelle-targeted aequorin luminescence (direct measurement of ER lumenal free Ca2+) in pmr1 null mutants vs. wild-type\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct quantitative in-organello Ca2+ measurement with genetic KO\",\n      \"pmids\": [\"10469652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"An N-terminal EF hand-like motif in Pmr1 binds Ca2+ (demonstrated with recombinant bacterial fusions) and modulates ion transport; point mutations D51A and D53A reduce Ca2+ transport affinity; the double mutant blocks ER exit; in-frame deletions abolish function; mutations also alter relative affinity for Ca2+ vs. Mn2+, and perturb proteolytic stability of the ATP-binding domain.\",\n      \"method\": \"Recombinant protein Ca2+-binding assay, site-directed mutagenesis, 45Ca2+ transport assay, ER exit/trafficking analysis, proteolytic stability assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assay plus mutagenesis plus functional transport assays\",\n      \"pmids\": [\"10545175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In the absence of Pmr1 (yeast ATP2C1 ortholog), compensatory calcineurin-dependent induction of the vacuolar Ca2+-ATPase Pmc1 occurs, together with increased H+/Ca2+ exchange activity, demonstrating that Pmr1 is the dominant Ca2+ pump under normal conditions and that loss of Pmr1 triggers a specific compensatory Ca2+ homeostasis response.\",\n      \"method\": \"Subcellular fractionation, Ca2+ transport activity assays, promoter-reporter assays, Western blotting, calcineurin inhibitor (FK506) treatment\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary methods linking Pmr1 loss to compensatory Ca2+ transport induction\",\n      \"pmids\": [\"10431803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mutations in ATP2C1, encoding a Ca2+ pump that sequesters calcium into the Golgi, cause Hailey-Hailey disease; cytoplasmic Ca2+ regulation is impaired in cultured keratinocytes from HHD patients, and the epidermal Ca2+ gradient is attenuated in vivo.\",\n      \"method\": \"Positional cloning, mutation identification in 21 kindreds, cytoplasmic Ca2+ measurements in cultured keratinocytes, in vivo Ca2+ gradient measurement\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational disease-gene paper with functional Ca2+ measurements, independently replicated\",\n      \"pmids\": [\"10615129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Transmembrane segment M6 residue Asp778 is essential for cation binding and transport by Pmr1; D778A abolishes Ca2+- and Mn2+-dependent ATP hydrolysis and phosphoenzyme formation from ATP, while reverse phosphorylation from Pi is preserved but insensitive to Ca2+ or Mn2+. Residue Gln783 in M6 is critical for Mn2+ selectivity; Q783A retains Ca2+-ATPase activity (Km ~0.06 µM) but Mn2+-ATPase is nearly abolished even at 10 µM Mn2+.\",\n      \"method\": \"Purified histidine-tagged Pmr1, in vitro ATPase assay, phosphoenzyme intermediate assay (forward from ATP and reverse from Pi), site-directed mutagenesis, molecular modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — purified protein, reconstituted enzymatic assays, mutagenesis with mechanistic resolution\",\n      \"pmids\": [\"10801856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Phenotypic screen of 35 transmembrane-domain mutations in Pmr1 identified residues in M4, M5, M6, M7, M8 critical for Ca2+ and/or Mn2+ transport; Class 2 (loss-of-function) mutants lacked 45Ca2+ transport; notably Asn774 and Asp778 in M6 are essential; Class 3 mutants (e.g., Q783A) show selective loss of Mn2+ transport, indicating differential ion selectivity determinants.\",\n      \"method\": \"Systematic mutagenesis, phenotypic growth assays (BAPTA and Mn2+ toxicity), 45Ca2+ transport assay, Golgi localization analysis, protein conformation assessment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis combined with functional transport assays\",\n      \"pmids\": [\"10801855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"C. elegans PMR1 (ATP2C1 ortholog) transports Ca2+ and Mn2+ with high affinity into the Golgi apparatus in a thapsigargin-insensitive manner when ectopically expressed in COS-1 cells; accumulated Ca2+ is releasable by IP3, establishing the Golgi as an IP3-sensitive Ca2+ store.\",\n      \"method\": \"Ectopic expression in permeabilized COS-1 cells, direct ion transport assay, IP3-triggered Ca2+ release measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct functional reconstitution of Ca2+ and Mn2+ transport in heterologous cells\",\n      \"pmids\": [\"11134055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human ATP2C1 (SPCA1) protein (~115 kDa) localizes to the Golgi apparatus in human keratinocytes; HHD keratinocytes with decreased SPCA1 protein show slower Golgi Ca2+ refill and significantly lower maximal intraorganelle Ca2+ concentration, measured with Golgi-targeted aequorin.\",\n      \"method\": \"Western blotting, immunofluorescence localization, organelle-targeted aequorin Ca2+ measurement in intact keratinocytes and in vivo\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct Golgi Ca2+ measurement using aequorin, localization confirmed, with disease-relevant functional consequence\",\n      \"pmids\": [\"14632183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SPCA1 (ATP2C1) is responsible for Ca2+ uptake in a subfraction of the Golgi in HeLa cells; RNAi knockdown of SPCA1 reduced Golgi lumenal Ca2+ as measured by Golgi-targeted aequorin; absence of SPCA1 reduced frequency of baseline Ca2+ oscillations but did not abolish them, indicating partial contribution to cytosolic Ca2+ signaling.\",\n      \"method\": \"RNA interference, Golgi-targeted aequorin Ca2+ measurement, cytosolic Ca2+ imaging\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi knockdown with direct organellar Ca2+ measurement\",\n      \"pmids\": [\"12804581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Packing interaction between Val335 in M4 and Gln783 in M6 of PMR1 is critical for Mn2+ transport selectivity; V335G mimics the Mn2+-selective defect of Q783A and V335I suppresses it; exchange of side chains at 335 and 783 produces ion selectivity defects, suggesting this region constitutes a conformation-sensitive gate for Mn2+ access.\",\n      \"method\": \"Scanning mutagenesis, cation-dependent ATPase assay with purified enzyme, phenotypic growth assays, homology modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — purified enzyme assays combined with systematic mutagenesis and suppressor analysis\",\n      \"pmids\": [\"12824173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ATP2C1/SPCA1 knockdown (siRNA) in pancreatic beta-cells reduces Ca2+ uptake into the ER and secretory vesicles by ~20% (measured with organelle-targeted aequorins), enhances L-type Ca2+ channel flux, and augments glucose-stimulated insulin secretion, demonstrating a functional role in beta-cell Ca2+ homeostasis and insulin secretion.\",\n      \"method\": \"siRNA knockdown, organelle-targeted aequorin Ca2+ measurement in permeabilized cells, intact cell Ca2+ imaging (fluo-3), insulin secretion assay, subcellular fractionation\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA KD with direct organellar Ca2+ measurement and defined physiological output\",\n      \"pmids\": [\"14747290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ATP2C1 deficiency (siRNA knockdown) impairs post-translational glycoprotein processing (wild-type thyroglobulin) and ER-associated degradation of misfolded thyroglobulin via the secretory pathway, while rendering cells hypersensitive to ER stress without constitutively activating the UPR (PERK, ATF6, or Ire1/XBP1 pathways unaffected).\",\n      \"method\": \"siRNA knockdown, metabolic labeling and pulse-chase for glycoprotein processing, ER stress induction and UPR pathway monitoring\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with multiple defined functional readouts in secretory pathway processing\",\n      \"pmids\": [\"15623514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Yeast Pmr1 functions upstream of Npr1 and Gln3 in opposition to Lst8 in TOR signaling; pmr1 deletion confers rapamycin resistance; Ca2+/Mn2+ ion homeostasis controlled by Pmr1 is required for normal TOR pathway signaling including nuclear translocation of Gln3 and Gap1 permease regulation.\",\n      \"method\": \"Genome-wide deletion screen for rapamycin resistance, epistasis analysis (double mutants), Gln3 reporter assays, plasma membrane permease localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established, but indirect link between Ca2+/Mn2+ and TOR requires further mechanistic resolution\",\n      \"pmids\": [\"17095607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Homozygous knockout of Atp2c1 in mice causes embryonic lethality by E10.5 with dilated Golgi membranes, fewer stacked leaflets, expanded Golgi amount, increased Golgi-associated vesicles, increased apoptosis, and large cytoplasmic lipid accumulation, demonstrating that SPCA1 is essential for Golgi structural integrity and lipid handling.\",\n      \"method\": \"Targeted gene knockout in mice, embryo histology, electron microscopy of Golgi ultrastructure, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with detailed ultrastructural and cell biological phenotyping\",\n      \"pmids\": [\"17597066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SPCA1 (ATP2C1) localizes to the juxtanuclear Golgi in N2a neuroblastoma cells; SPCA1 knockdown by RNAi impairs Golgi Ca2+ homeostasis, delays neuronal differentiation (increased neurite number, reduced length), and disrupts protein trafficking including Golgi-localized and plasma membrane-targeted constructs; in hippocampal neurons, SPCA1 is differentially distributed in Golgi stacks depending on differentiation stage.\",\n      \"method\": \"RNAi knockdown, Ca2+ imaging (Golgi-targeted cameleon), live imaging of trafficking markers, immunocytochemistry, primary neuron culture\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi KD with direct Golgi Ca2+ measurement, trafficking assays, and defined differentiation phenotype\",\n      \"pmids\": [\"19793975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SPCA1 (ATP2C1) inhibition in MDA-MB-231 basal-like breast cancer cells alters calcium-dependent proprotein convertase activity in the secretory pathway, causing defective processing of pro-IGF1R to functional IGF1Rβ and accumulation of inactive trans-Golgi network pro-IGF1R, without global alterations in cytosolic Ca2+ signaling.\",\n      \"method\": \"SPCA1 inhibition, 3D culture morphology assay, Western blotting for IGF1R processing intermediates, Ca2+ imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological inhibition with defined substrate processing readout; no genetic rescue\",\n      \"pmids\": [\"20837466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SPCA1 is located predominantly on lateral rims of Golgi cisternae, tubular non-compact zones interconnecting Golgi stacks, and tubular TGN regions (not the core of cisternae); SPCA1 knockdown causes Golgi fragmentation (loss of cis-most and trans-most cisternae), inhibits exit of VSV-G from the Golgi, and delays retrograde redistribution of glycosylation enzymes by brefeldin A, establishing SPCA1 as essential for intra-Golgi transport and ribbon maintenance.\",\n      \"method\": \"Immunoelectron microscopy for precise Golgi localization, RNAi knockdown, VSV-G trafficking assay, brefeldin A redistribution assay\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — precise ultrastructural localization combined with RNAi and multiple trafficking readouts\",\n      \"pmids\": [\"20604898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PMR-1 (C. elegans ortholog of ATP2C1/SPCA1) plays an essential role in embryonic cell migration; pmr-1 mutants show reduced migration rates of ventral neuroblasts and other blastomeres; genetic interaction with itr-1/IP3R and unc-68/RyR (Ca2+ channels) modulates embryonic lethality, placing pmr-1 in a Ca2+ homeostasis network that regulates cytoskeletal dynamics during gastrulation.\",\n      \"method\": \"Genetic screens, live imaging of cell migration, gene interaction (double mutant) analysis with IP3R and RyR\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis plus live imaging with quantified migration rates\",\n      \"pmids\": [\"23696750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cofilin-1 (CFL-1) recruits F-actin to the phosphorylation domain (P-domain) of SPCA1 at the TGN; a 132-aa portion of the SPCA1 P-domain interacts with actin in a CFL-1-dependent manner; mutagenesis of the CFL-1-binding site in SPCA1 impairs Ca2+ entry into the TGN and secretory cargo sorting; expression of the P-domain in HeLa cells acts as a dominant-negative for TGN Ca2+ import and cargo sorting.\",\n      \"method\": \"Purified protein interaction assay, F-actin co-sedimentation with Ni-NTA agarose beads, site-directed mutagenesis, dominant-negative expression in HeLa cells, TGN Ca2+ measurement, cargo sorting assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — purified protein interaction assay combined with mutagenesis and functional cellular readouts\",\n      \"pmids\": [\"25179631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SPCA1 (ATP2C1) calcium transport activity is required for maturation of diverse viral glycoproteins (measles, dengue, West Nile, Zika, chikungunya); SPCA1-deficient cells fail to proteolytically mature viral glycoproteins via trans-Golgi network proteases that require Ca2+ for activity, preventing viral spread.\",\n      \"method\": \"Genome-wide haploid cell knockout screen, genetic KO validation, viral spread assays, glycoprotein maturation Western blotting\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen plus clean KO with defined biochemical mechanism (Ca2+-dependent protease activity)\",\n      \"pmids\": [\"29024641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SPCA1 activity at the TGN is controlled by sphingomyelin content; local sphingomyelin synthesis promotes Ca2+ flux into TGN lumen via SPCA1; SPCA1-driven Ca2+ release enables Ca2+-binding protein Cab45 to oligomerize and package specific secreted proteins into sphingomyelin-enriched vesicular carriers, coupling sphingomyelin synthesis to secretory protein sorting.\",\n      \"method\": \"Genetic perturbation of sphingomyelin synthesis, Ca2+ imaging at TGN, Cab45 oligomerization assay, vesicle isolation and cargo analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking SPCA1 Ca2+ transport to lipid synthesis and cargo sorting\",\n      \"pmids\": [\"30393074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of Spca1 in mouse neuroepithelial cells causes failure of apical constriction (not cell death), associated with disrupted myosin II localization, impaired actin dynamics, and mislocalization of cofilin-1, leading to cranial exencephaly and spinal cord defects during neural tube closure.\",\n      \"method\": \"Novel Spca1 mouse allele (KO), live imaging of neuroepithelial cell shape, myosin II and cofilin-1 immunofluorescence localization, actin dynamics analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with mechanistic dissection of cytoskeletal effectors\",\n      \"pmids\": [\"30228103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SPCA1 overexpression induces store-independent Ca2+ entry (SICE) via functional coupling with Orai1 at the plasma membrane (TIRF co-localization), independently of STIM1; this elevates cytosolic and non-ER store Ca2+ and induces Golgi swelling with TFE3 nuclear translocation (Golgi stress marker); HHD-associated SPCA1 mutations impair Ca2+ transport, Orai1 activation, or both.\",\n      \"method\": \"SPCA1 overexpression, Orai1 RNAi knockdown, TIRF microscopy co-localization, cytosolic Ca2+ and non-ER store Ca2+ measurement, Golgi morphology analysis, TFE3 translocation assay, functional analysis of HHD mutations\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — overexpression and KD with multiple readouts; interaction mechanism not reconstituted in vitro\",\n      \"pmids\": [\"29555205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The N-terminal EF-hand-like motif of SPCA1a (absent in SPCA2) binds Ca2+ and regulates pump activity; mutation of this motif lowers Ca2+ turnover rate relative to Mn2+, increases substrate affinity, and reduces biphasic activation of SPCA1a; Ca2+ binding to this motif promotes SPCA1a autophosphorylation, especially relevant at high Ca2+ load or low ATP.\",\n      \"method\": \"Purified recombinant SPCA1a and SPCA2 from yeast expression system, in vitro ATPase assay, autophosphorylation assay, Ca2+-binding assay, mutagenesis of EF-hand motif\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — purified protein biochemistry with mutagenesis and multiple functional assays\",\n      \"pmids\": [\"30923126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TMEM165 stability and Golgi localization is directly dependent on SPCA1 Mn2+-pumping activity; SPCA1-deficient cells show constitutive lysosomal degradation of TMEM165; only SPCA1 mutant Q747A (favoring Mn2+ pumping) rescues TMEM165 abundance, establishing that SPCA1-mediated Mn2+ transport into the Golgi is necessary to maintain TMEM165.\",\n      \"method\": \"SPCA1 KO (Hap1 cells), SPCA1 mutant complementation, TMEM165 localization by immunofluorescence, lysosomal degradation assay, SERCA2b overexpression rescue\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with mechanistic rescue using transport-selective mutants\",\n      \"pmids\": [\"31652305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of human SPCA1 (hSPCA1) in six intermediate states reveal a near-complete Ca2+ transport conformational cycle; hSPCA1 undergoes unique conformational changes during ATP binding and phosphorylation compared to other P-type II ATPases; separation of transmembrane helices 4L and 6 causes Ca2+-binding site distortion enabling a distinct Ca2+ release mechanism; the CaE2P state of P-type IIA ATPases was directly visualized.\",\n      \"method\": \"Cryo-electron microscopy (6 structures at multiple states), molecular dynamics simulations, structural analysis of transmembrane helix movements\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple cryo-EM structures resolving the conformational cycle with MD simulation validation\",\n      \"pmids\": [\"37258749\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP2C1 encodes SPCA1, a P-type Ca2+/Mn2+-ATPase that localizes to the Golgi apparatus (especially the trans-Golgi network lateral rims and TGN tubules), where it uses ATP hydrolysis via a phosphoenzyme intermediate to actively pump cytosolic Ca2+ and Mn2+ into the Golgi lumen; Ca2+ transport is modulated by an N-terminal EF-hand-like motif that binds Ca2+ to promote autophosphorylation, and by cofilin-1-dependent recruitment of F-actin to the P-domain; Golgi lumenal Ca2+ supplied by SPCA1 drives Ca2+-dependent protein processing (glycosylation, proprotein convertase activity, viral glycoprotein maturation), Cab45-mediated oligomerization and selective secretory cargo sorting into sphingomyelin-enriched TGN vesicles, and cytoskeletal contractility (via myosin II and cofilin-1) required for neural tube closure; loss of one functional copy causes Hailey-Hailey disease through haploinsufficiency-driven impairment of cytoplasmic Ca2+ regulation in keratinocytes, while complete loss causes embryonic lethality associated with Golgi structural disruption and increased apoptosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATP2C1 encodes SPCA1, a P-type Ca²⁺/Mn²⁺-ATPase that localizes to the lateral rims and tubular regions of the Golgi apparatus, where it uses ATP hydrolysis via a phosphoenzyme intermediate to actively transport cytosolic Ca²⁺ and Mn²⁺ into the Golgi lumen, thereby maintaining Golgi ion homeostasis essential for protein glycosylation, proprotein convertase-dependent processing, secretory cargo sorting, and Golgi ribbon integrity [PMID:9092527, PMID:20604898, PMID:30393074, PMID:30923126]. Golgi lumenal Ca²⁺ supplied by SPCA1 drives Cab45-mediated oligomerization for selective cargo packaging into sphingomyelin-enriched TGN vesicles, supports Ca²⁺-dependent maturation of viral glycoproteins, and regulates cytoskeletal contractility through cofilin-1 and myosin II during neural tube closure [PMID:30393074, PMID:29024641, PMID:25179631, PMID:30228103]. An N-terminal EF-hand-like motif binds Ca²⁺ to promote autophosphorylation and modulate transport kinetics, while transmembrane residues Asp778 and Gln783 are critical determinants of Ca²⁺ versus Mn²⁺ selectivity [PMID:30923126, PMID:10801856, PMID:12824173]. Loss-of-function mutations in one copy of ATP2C1 cause Hailey-Hailey disease through haploinsufficiency-driven impairment of Ca²⁺ homeostasis in keratinocytes, while homozygous loss causes embryonic lethality with Golgi structural disruption [PMID:10615129, PMID:17597066].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Identification of PMR1 as the founding member of a distinct P-type ATPase subfamily acting in the secretory pathway established that an active Ca²⁺ pump is required upstream of Golgi-dependent processing events.\",\n      \"evidence\": \"Genetic suppressor screen (ypt1-1 rescue) and sequence analysis in S. cerevisiae\",\n      \"pmids\": [\"2526682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subcellular localization not yet determined\", \"Ion specificity (Ca²⁺ vs. Mn²⁺) not resolved\", \"No mammalian ortholog yet identified\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Direct localization of PMR1 to a Golgi-like compartment linked its Ca²⁺-pumping function to Golgi-dependent proteolytic processing and glycosylation.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence co-localization with Golgi markers, and phenotypic rescue by extracellular Ca²⁺ in yeast\",\n      \"pmids\": [\"1379856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transport activity not directly measured\", \"Whether PMR1 also transports Mn²⁺ not tested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Reconstitution of ATP-dependent ⁴⁵Ca²⁺ transport and demonstration that active-site Asp371 is required for catalysis established PMR1 as a bona fide Ca²⁺-transporting ATPase biochemically distinct from SERCA and PMCA.\",\n      \"evidence\": \"In vitro ⁴⁵Ca²⁺ uptake in Golgi-enriched fractions, active-site mutagenesis, and inhibitor profiling in yeast\",\n      \"pmids\": [\"9092527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mn²⁺ transport not biochemically demonstrated\", \"No structural information\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that PMR1 supplies both Ca²⁺ and Mn²⁺ to the secretory pathway expanded its role beyond Ca²⁺ homeostasis to include Mn²⁺-dependent glycosylation and protein quality control.\",\n      \"evidence\": \"Genetic complementation with SERCA, ion supplementation rescue of pmr1Δ glycosylation and sorting defects\",\n      \"pmids\": [\"9571246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of Ca²⁺ vs. Mn²⁺ to individual downstream processes not separated\", \"Mammalian dual-ion transport not yet shown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Quantitative measurement of ER/Golgi lumenal Ca²⁺ and identification of an N-terminal EF-hand-like regulatory motif revealed that PMR1 is the dominant Ca²⁺ pump maintaining secretory pathway stores and that its activity is autoregulated by Ca²⁺ binding.\",\n      \"evidence\": \"Organelle-targeted aequorin in pmr1Δ yeast (PMID:10469652); recombinant Ca²⁺-binding assays and mutagenesis of the EF-hand motif (PMID:10545175); compensatory induction of vacuolar pumps upon PMR1 loss (PMID:10431803)\",\n      \"pmids\": [\"10469652\", \"10545175\", \"10431803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the EF-hand motif functions identically in the mammalian ortholog\", \"Structural basis of EF-hand regulation unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Positional cloning of ATP2C1 mutations in Hailey-Hailey disease families, combined with demonstration of impaired keratinocyte Ca²⁺ regulation, established haploinsufficiency of the human Golgi Ca²⁺ pump as the cause of this genodermatosis.\",\n      \"evidence\": \"Mutation identification in 21 HHD kindreds, cytoplasmic Ca²⁺ measurements in patient keratinocytes, in vivo epidermal Ca²⁺ gradient measurement\",\n      \"pmids\": [\"10615129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking Golgi Ca²⁺ deficit to keratinocyte adhesion failure not resolved\", \"Genotype-phenotype correlations not established\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Systematic mutagenesis of transmembrane helices identified Asp778 as essential for both Ca²⁺ and Mn²⁺ transport and Gln783 as a selective determinant of Mn²⁺ binding, defining the ion selectivity filter of the SPCA family.\",\n      \"evidence\": \"Purified Pmr1 ATPase and phosphoenzyme assays with D778A and Q783A mutants (PMID:10801856); phenotypic screen of 35 TM mutations with ⁴⁵Ca²⁺ transport (PMID:10801855); C. elegans PMR1 reconstitution in COS-1 cells confirming dual Ca²⁺/Mn²⁺ transport (PMID:11134055)\",\n      \"pmids\": [\"10801856\", \"10801855\", \"11134055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the ion-binding site\", \"How Gln783–Val335 packing controls gating only partially resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Direct Golgi-targeted aequorin measurements in human keratinocytes and HeLa cells confirmed that SPCA1 is the principal Ca²⁺ pump maintaining Golgi lumenal Ca²⁺ stores in mammalian cells, and that HHD patient cells have reduced Golgi Ca²⁺.\",\n      \"evidence\": \"Golgi-targeted aequorin in HHD vs. control keratinocytes (PMID:14632183); SPCA1 RNAi in HeLa with Golgi Ca²⁺ readout (PMID:12804581)\",\n      \"pmids\": [\"14632183\", \"12804581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of SPCA1 vs. SERCA to Golgi Ca²⁺ filling not fully quantified\", \"Packing interaction between V335 and Q783 only confirmed with yeast enzyme (PMID:12824173)\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"SPCA1 knockdown impaired glycoprotein processing, ER-associated degradation, and insulin secretion, demonstrating that SPCA1-supplied Golgi Ca²⁺/Mn²⁺ is broadly required for secretory pathway quality control and regulated exocytosis.\",\n      \"evidence\": \"siRNA in pancreatic beta-cells with organelle-targeted aequorin and insulin secretion assay (PMID:14747290); siRNA in thyroid cells with pulse-chase glycoprotein processing and UPR monitoring (PMID:15623514)\",\n      \"pmids\": [\"14747290\", \"15623514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ca²⁺ or Mn²⁺ depletion is the primary driver of each phenotype not separated\", \"Beta-cell phenotype not confirmed in genetic KO models\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Immuno-EM revealed SPCA1 concentrates on lateral rims and tubular non-compact zones of the Golgi, and its loss causes Golgi fragmentation, blocked anterograde/retrograde transport, and defective proprotein convertase-dependent processing of IGF1R.\",\n      \"evidence\": \"Immunoelectron microscopy localization, RNAi with VSV-G and BFA trafficking assays (PMID:20604898); SPCA1 inhibition with IGF1R processing readout in breast cancer cells (PMID:20837466)\",\n      \"pmids\": [\"20604898\", \"20837466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What retains SPCA1 at lateral rims vs. cisternal cores unknown\", \"IGF1R processing result based on pharmacological inhibition without genetic rescue\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that cofilin-1 recruits F-actin to the SPCA1 P-domain to regulate TGN Ca²⁺ import and cargo sorting revealed an unexpected cytoskeletal–ion pump coupling mechanism at the TGN.\",\n      \"evidence\": \"Purified protein interaction assay, F-actin co-sedimentation, mutagenesis of CFL1-binding site, dominant-negative P-domain expression in HeLa cells\",\n      \"pmids\": [\"25179631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of actin–P-domain interaction unknown\", \"Whether cofilin-1 modulates Mn²⁺ transport not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genome-wide screens identified SPCA1 as essential for maturation of diverse viral glycoproteins, establishing Golgi Ca²⁺-dependent protease activity as a host dependency factor exploited by multiple enveloped viruses.\",\n      \"evidence\": \"Haploid cell KO screen, genetic KO validation, viral spread assays and glycoprotein maturation blots for measles, dengue, Zika, chikungunya, West Nile\",\n      \"pmids\": [\"29024641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific Ca²⁺-dependent proteases responsible not identified for all viruses\", \"In vivo relevance for viral pathogenesis not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"SPCA1 was placed at the nexus of sphingomyelin-dependent Ca²⁺ signaling and selective secretory sorting: local SM synthesis activates SPCA1-mediated Ca²⁺ flux, enabling Cab45 oligomerization and cargo packaging, while in neuroepithelium SPCA1 loss disrupts myosin II and cofilin-1 localization causing neural tube closure failure.\",\n      \"evidence\": \"SM synthesis perturbation with TGN Ca²⁺ imaging and Cab45 oligomerization assay (PMID:30393074); Spca1 KO mouse with live imaging of neuroepithelial cell shape and cytoskeletal localization (PMID:30228103)\",\n      \"pmids\": [\"30393074\", \"30228103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SM content modulates SPCA1 activity (direct lipid–protein interaction vs. membrane property) not resolved\", \"Whether neural tube defect is Ca²⁺- or Mn²⁺-dependent not distinguished\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Purified SPCA1a biochemistry confirmed the N-terminal EF-hand promotes autophosphorylation and tunes Ca²⁺/Mn²⁺ selectivity, while SPCA1-dependent Mn²⁺ delivery to the Golgi was shown to be specifically required for TMEM165 stability.\",\n      \"evidence\": \"Purified recombinant SPCA1a ATPase/autophosphorylation assays with EF-hand mutants (PMID:30923126); SPCA1 KO Hap1 cells rescued by Mn²⁺-selective mutant Q747A restoring TMEM165 (PMID:31652305)\",\n      \"pmids\": [\"30923126\", \"31652305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EF-hand regulation operates in vivo at physiological Ca²⁺ concentrations not confirmed\", \"How Mn²⁺ depletion triggers TMEM165 lysosomal degradation mechanistically unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cryo-EM structures of human SPCA1 across six transport intermediates revealed a near-complete conformational cycle, identifying unique TM4L–TM6 separation as the mechanism for Ca²⁺ release and directly visualizing the CaE2P state for the first time in a P-type IIA ATPase.\",\n      \"evidence\": \"Cryo-EM at multiple conformational states with molecular dynamics simulations\",\n      \"pmids\": [\"37258749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure with Mn²⁺ bound; Mn²⁺ transport mechanism not structurally resolved\", \"EF-hand domain not resolved in structures\", \"Lipid interactions at the TM domain not captured\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SPCA1-mediated Golgi Ca²⁺/Mn²⁺ supply is differentially decoded by downstream effectors in distinct cell types, and the structural basis for sphingomyelin- and cofilin-1-dependent regulation of SPCA1 activity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of SPCA1 with Mn²⁺ bound or with the EF-hand domain resolved\", \"Mechanism by which sphingomyelin modulates SPCA1 (direct vs. indirect) unknown\", \"How Golgi Ca²⁺ deficit specifically impairs keratinocyte adhesion in HHD not molecularly defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [2, 8, 27, 29]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2, 3, 10, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 11, 12, 18, 20, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 10, 11, 14]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [20, 22, 24]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 15, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 23]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CFL1\",\n      \"ORAI1\",\n      \"TMEM165\",\n      \"CAB45\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}