Affinage

ATP2C1

Calcium-transporting ATPase type 2C member 1 · UniProt P98194

Length
919 aa
Mass
100.6 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1989 High

    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

    PMID:2526682

    Open questions at the time
    • Subcellular localization not yet determined
    • Ion specificity (Ca²⁺ vs. Mn²⁺) not resolved
    • No mammalian ortholog yet identified
  2. 1992 High

    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

    PMID:1379856

    Open questions at the time
    • Transport activity not directly measured
    • Whether PMR1 also transports Mn²⁺ not tested
  3. 1997 High

    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

    PMID:9092527

    Open questions at the time
    • Mn²⁺ transport not biochemically demonstrated
    • No structural information
  4. 1998 High

    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

    PMID:9571246

    Open questions at the time
    • Relative contributions of Ca²⁺ vs. Mn²⁺ to individual downstream processes not separated
    • Mammalian dual-ion transport not yet shown
  5. 1999 High

    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)

    PMID:10431803 PMID:10469652 PMID:10545175

    Open questions at the time
    • Whether the EF-hand motif functions identically in the mammalian ortholog
    • Structural basis of EF-hand regulation unknown
  6. 2000 High

    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

    PMID:10615129

    Open questions at the time
    • Molecular mechanism linking Golgi Ca²⁺ deficit to keratinocyte adhesion failure not resolved
    • Genotype-phenotype correlations not established
  7. 2000 High

    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)

    PMID:10801855 PMID:10801856 PMID:11134055

    Open questions at the time
    • No high-resolution structure of the ion-binding site
    • How Gln783–Val335 packing controls gating only partially resolved
  8. 2003 High

    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)

    PMID:12804581 PMID:14632183

    Open questions at the time
    • 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)
  9. 2004 High

    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)

    PMID:14747290 PMID:15623514

    Open questions at the time
    • Whether Ca²⁺ or Mn²⁺ depletion is the primary driver of each phenotype not separated
    • Beta-cell phenotype not confirmed in genetic KO models
  10. 2010 High

    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)

    PMID:20604898 PMID:20837466

    Open questions at the time
    • What retains SPCA1 at lateral rims vs. cisternal cores unknown
    • IGF1R processing result based on pharmacological inhibition without genetic rescue
  11. 2014 High

    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

    PMID:25179631

    Open questions at the time
    • Structural basis of actin–P-domain interaction unknown
    • Whether cofilin-1 modulates Mn²⁺ transport not tested
  12. 2017 High

    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

    PMID:29024641

    Open questions at the time
    • Specific Ca²⁺-dependent proteases responsible not identified for all viruses
    • In vivo relevance for viral pathogenesis not tested
  13. 2018 High

    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)

    PMID:30228103 PMID:30393074

    Open questions at the time
    • 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
  14. 2019 High

    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)

    PMID:30923126 PMID:31652305

    Open questions at the time
    • Whether EF-hand regulation operates in vivo at physiological Ca²⁺ concentrations not confirmed
    • How Mn²⁺ depletion triggers TMEM165 lysosomal degradation mechanistically unclear
  15. 2023 High

    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

    PMID:37258749

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140657 ATP-dependent activity 4 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005794 Golgi apparatus 6
Pathway
R-HSA-382551 Transport of small molecules 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-9609507 Protein localization 3 R-HSA-1643685 Disease 2
Partners
CAB45CFL1ORAI1TMEM165

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 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. Genetic epistasis (suppressor screen, ypt1-1 rescue), sequence comparison, functional phenotypic analysis Cell High 2526682
1992 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. Subcellular fractionation, indirect immunofluorescence, double-label co-localization, genetic epistasis with sec mutants, Ca2+ rescue experiments Molecular biology of the cell High 1379856
1997 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. In vitro Ca2+ transport assay (45Ca2+ uptake), active-site mutagenesis (Asp-371→Glu/Asn), sucrose gradient fractionation, inhibitor profiling The Journal of biological chemistry High 9092527
1998 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. Genetic complementation (SERCA expression rescue), phenotypic analysis of pmr1 mutants, ion supplementation experiments Molecular biology of the cell High 9571246
1999 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. Organelle-targeted aequorin luminescence (direct measurement of ER lumenal free Ca2+) in pmr1 null mutants vs. wild-type The EMBO journal High 10469652
1999 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. Recombinant protein Ca2+-binding assay, site-directed mutagenesis, 45Ca2+ transport assay, ER exit/trafficking analysis, proteolytic stability assay Biochemistry High 10545175
1999 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. Subcellular fractionation, Ca2+ transport activity assays, promoter-reporter assays, Western blotting, calcineurin inhibitor (FK506) treatment FEBS letters High 10431803
2000 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. Positional cloning, mutation identification in 21 kindreds, cytoplasmic Ca2+ measurements in cultured keratinocytes, in vivo Ca2+ gradient measurement Nature genetics High 10615129
2000 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+. Purified histidine-tagged Pmr1, in vitro ATPase assay, phosphoenzyme intermediate assay (forward from ATP and reverse from Pi), site-directed mutagenesis, molecular modeling The Journal of biological chemistry High 10801856
2000 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. Systematic mutagenesis, phenotypic growth assays (BAPTA and Mn2+ toxicity), 45Ca2+ transport assay, Golgi localization analysis, protein conformation assessment The Journal of biological chemistry High 10801855
2000 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. Ectopic expression in permeabilized COS-1 cells, direct ion transport assay, IP3-triggered Ca2+ release measurement The Journal of biological chemistry High 11134055
2003 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. Western blotting, immunofluorescence localization, organelle-targeted aequorin Ca2+ measurement in intact keratinocytes and in vivo The Journal of investigative dermatology High 14632183
2003 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. RNA interference, Golgi-targeted aequorin Ca2+ measurement, cytosolic Ca2+ imaging Biochemical and biophysical research communications High 12804581
2003 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. Scanning mutagenesis, cation-dependent ATPase assay with purified enzyme, phenotypic growth assays, homology modeling The Journal of biological chemistry High 12824173
2004 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. siRNA knockdown, organelle-targeted aequorin Ca2+ measurement in permeabilized cells, intact cell Ca2+ imaging (fluo-3), insulin secretion assay, subcellular fractionation Diabetes High 14747290
2004 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). siRNA knockdown, metabolic labeling and pulse-chase for glycoprotein processing, ER stress induction and UPR pathway monitoring The Journal of biological chemistry High 15623514
2006 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. Genome-wide deletion screen for rapamycin resistance, epistasis analysis (double mutants), Gln3 reporter assays, plasma membrane permease localization Proceedings of the National Academy of Sciences of the United States of America Medium 17095607
2007 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. Targeted gene knockout in mice, embryo histology, electron microscopy of Golgi ultrastructure, apoptosis assays The Journal of biological chemistry High 17597066
2009 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. RNAi knockdown, Ca2+ imaging (Golgi-targeted cameleon), live imaging of trafficking markers, immunocytochemistry, primary neuron culture The Journal of neuroscience High 19793975
2010 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. SPCA1 inhibition, 3D culture morphology assay, Western blotting for IGF1R processing intermediates, Ca2+ imaging The Journal of biological chemistry Medium 20837466
2010 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. Immunoelectron microscopy for precise Golgi localization, RNAi knockdown, VSV-G trafficking assay, brefeldin A redistribution assay Traffic High 20604898
2013 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. Genetic screens, live imaging of cell migration, gene interaction (double mutant) analysis with IP3R and RyR PLoS genetics High 23696750
2014 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. 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 The Journal of cell biology High 25179631
2017 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. Genome-wide haploid cell knockout screen, genetic KO validation, viral spread assays, glycoprotein maturation Western blotting Cell host & microbe High 29024641
2018 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. Genetic perturbation of sphingomyelin synthesis, Ca2+ imaging at TGN, Cab45 oligomerization assay, vesicle isolation and cargo analysis Developmental cell High 30393074
2018 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. Novel Spca1 mouse allele (KO), live imaging of neuroepithelial cell shape, myosin II and cofilin-1 immunofluorescence localization, actin dynamics analysis Development High 30228103
2018 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. 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 Biochimica et biophysica acta. Molecular cell research Medium 29555205
2019 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. Purified recombinant SPCA1a and SPCA2 from yeast expression system, in vitro ATPase assay, autophosphorylation assay, Ca2+-binding assay, mutagenesis of EF-hand motif The Journal of biological chemistry High 30923126
2019 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. SPCA1 KO (Hap1 cells), SPCA1 mutant complementation, TMEM165 localization by immunofluorescence, lysosomal degradation assay, SERCA2b overexpression rescue The Biochemical journal High 31652305
2023 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. Cryo-electron microscopy (6 structures at multiple states), molecular dynamics simulations, structural analysis of transmembrane helix movements Cell research High 37258749

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1989 The yeast secretory pathway is perturbed by mutations in PMR1, a member of a Ca2+ ATPase family. Cell 473 2526682
2000 Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nature genetics 415 10615129
1992 The yeast Ca(2+)-ATPase homologue, PMR1, is required for normal Golgi function and localizes in a novel Golgi-like distribution. Molecular biology of the cell 378 1379856
1998 The medial-Golgi ion pump Pmr1 supplies the yeast secretory pathway with Ca2+ and Mn2+ required for glycosylation, sorting, and endoplasmic reticulum-associated protein degradation. Molecular biology of the cell 333 9571246
2000 Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump. Human molecular genetics 247 10767338
1995 Mutations in PMR1 suppress oxidative damage in yeast cells lacking superoxide dismutase. Molecular and cellular biology 213 7862131
1997 PMR1, a Ca2+-ATPase in yeast Golgi, has properties distinct from sarco/endoplasmic reticulum and plasma membrane calcium pumps. The Journal of biological chemistry 208 9092527
2003 Human keratinocyte ATP2C1 localizes to the Golgi and controls Golgi Ca2+ stores. The Journal of investigative dermatology 120 14632183
1999 Steady-state free Ca(2+) in the yeast endoplasmic reticulum reaches only 10 microM and is mainly controlled by the secretory pathway pump pmr1. The EMBO journal 111 10469652
2007 Loss of the Atp2c1 secretory pathway Ca(2+)-ATPase (SPCA1) in mice causes Golgi stress, apoptosis, and midgestational death in homozygous embryos and squamous cell tumors in adult heterozygotes. The Journal of biological chemistry 102 17597066
2000 Manganese selectivity of pmr1, the yeast secretory pathway ion pump, is defined by residue gln783 in transmembrane segment 6. Residue Asp778 is essential for cation transport. The Journal of biological chemistry 92 10801856
2003 PMR1/SPCA Ca2+ pumps and the role of the Golgi apparatus as a Ca2+ store. Pflugers Archiv : European journal of physiology 83 12739151
2004 SPCA1 pumps and Hailey-Hailey disease. Biochemical and biophysical research communications 82 15336968
2009 Identification of microRNA profiles in docetaxel-resistant human non-small cell lung carcinoma cells (SPC-A1). Journal of cellular and molecular medicine 77 19900214
2003 The contribution of the SPCA1 Ca2+ pump to the Ca2+ accumulation in the Golgi apparatus of HeLa cells assessed via RNA-mediated interference. Biochemical and biophysical research communications 75 12804581
2000 The Golgi PMR1 P-type ATPase of Caenorhabditis elegans. Identification of the gene and demonstration of calcium and manganese transport. The Journal of biological chemistry 74 11134055
1996 Overexpression of binding protein and disruption of the PMR1 gene synergistically stimulate secretion of bovine prochymosin but not plant thaumatin in yeast. Applied microbiology and biotechnology 73 8987725
2004 Role for plasma membrane-related Ca2+-ATPase-1 (ATP2C1) in pancreatic beta-cell Ca2+ homeostasis revealed by RNA silencing. Diabetes 71 14747290
2010 Golgi calcium pump secretory pathway calcium ATPase 1 (SPCA1) is a key regulator of insulin-like growth factor receptor (IGF1R) processing in the basal-like breast cancer cell line MDA-MB-231. The Journal of biological chemistry 68 20837466
2002 Hailey-Hailey disease: molecular and clinical characterization of novel mutations in the ATP2C1 gene. The Journal of investigative dermatology 68 11841554
2005 Secretory pathway Ca(2+)-ATPase (SPCA1) Ca(2)+ pumps, not SERCAs, regulate complex [Ca(2+)](i) signals in human spermatozoa. Journal of cell science 62 15811949
2012 The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca(2+) levels to α-synuclein toxicity in Parkinson's disease models. Cell death and differentiation 60 23154387
2018 Activity of the SPCA1 Calcium Pump Couples Sphingomyelin Synthesis to Sorting of Secretory Proteins in the Trans-Golgi Network. Developmental cell 57 30393074
1996 Elevated cytosolic free Ca2+ concentrations and massive Ca2+ accumulation within vacuoles, in yeast mutant lacking PMR1, a homolog of Ca2+ -ATPase. FEBS letters 57 8772202
2009 Silencing the SPCA1 (secretory pathway Ca2+-ATPase isoform 1) impairs Ca2+ homeostasis in the Golgi and disturbs neural polarity. The Journal of neuroscience : the official journal of the Society for Neuroscience 56 19793975
2000 Phenotypic screening of mutations in Pmr1, the yeast secretory pathway Ca2+/Mn2+-ATPase, reveals residues critical for ion selectivity and transport. The Journal of biological chemistry 55 10801855
2010 The SPCA1 Ca2+ pump and intracellular membrane trafficking. Traffic (Copenhagen, Denmark) 54 20604898
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2013 ESCRT components regulate the expression of the ER/Golgi calcium pump gene PMR1 through the Rim101/Nrg1 pathway in budding yeast. Journal of molecular cell biology 53 23933635
1999 Induction of vacuolar Ca2+-ATPase and H+/Ca2+ exchange activity in yeast mutants lacking Pmr1, the Golgi Ca2+-ATPase. FEBS letters 53 10431803
1999 An N-terminal EF hand-like motif modulates ion transport by Pmr1, the yeast Golgi Ca(2+)/Mn(2+)-ATPase. Biochemistry 52 10545175
2017 Diverse Viruses Require the Calcium Transporter SPCA1 for Maturation and Spread. Cell host & microbe 50 29024641
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2004 Deficiency of ATP2C1, a Golgi ion pump, induces secretory pathway defects in endoplasmic reticulum (ER)-associated degradation and sensitivity to ER stress. The Journal of biological chemistry 49 15623514
2017 Mutations in PMR1 stimulate xylose isomerase activity and anaerobic growth on xylose of engineered Saccharomyces cerevisiae by influencing manganese homeostasis. Scientific reports 48 28401919
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2003 Similar Ca(2+)-signaling properties in keratinocytes and in COS-1 cells overexpressing the secretory-pathway Ca(2+)-ATPase SPCA1. Cell calcium 45 12810057
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2005 Effects of ultraviolet B irradiation, proinflammatory cytokines and raised extracellular calcium concentration on the expression of ATP2A2 and ATP2C1. The British journal of dermatology 40 15840101
2017 Zebrafish slc30a10 deficiency revealed a novel compensatory mechanism of Atp2c1 in maintaining manganese homeostasis. PLoS genetics 38 28692648
2005 Effects of drugs and anticytokine antibodies on expression of ATP2A2 and ATP2C1 in cultured normal human keratinocytes. The British journal of dermatology 37 15888147
2014 Cofilin recruits F-actin to SPCA1 and promotes Ca2+-mediated secretory cargo sorting. The Journal of cell biology 36 25179631
2013 Enhancement of (-)-epigallocatechin-3-gallate and theaflavin-3-3'-digallate induced apoptosis by ascorbic acid in human lung adenocarcinoma SPC-A-1 cells and esophageal carcinoma Eca-109 cells via MAPK pathways. Biochemical and biophysical research communications 36 23892041
2004 Endonuclease-mediated mRNA decay involves the selective targeting of PMR1 to polyribosome-bound substrate mRNA. Molecular cell 34 15149593
2006 Pmr1, a Golgi Ca2+/Mn2+-ATPase, is a regulator of the target of rapamycin (TOR) signaling pathway in yeast. Proceedings of the National Academy of Sciences of the United States of America 33 17095607
2002 Mutation analysis of ATP2C1 gene in Taiwanese patients with Hailey-Hailey disease. The British journal of dermatology 33 11966689
2011 Oleanolic acid from Prunella Vulgaris L. induces SPC-A-1 cell line apoptosis via regulation of Bax, Bad and Bcl-2 expression. Asian Pacific journal of cancer prevention : APJCP 32 21545203
2005 Transcriptional regulation of ATP2C1 gene by Sp1 and YY1 and reduced function of its promoter in Hailey-Hailey disease keratinocytes. The Journal of investigative dermatology 32 15955096
2001 Mutation in PMR1, a Ca(2+)-ATPase in Golgi, confers salt tolerance in Saccharomyces cerevisiae by inducing expression of PMR2, an Na(+)-ATPase in plasma membrane. The Journal of biological chemistry 32 11387321
2008 The Pmr1 protein, the major yeast Ca2+-ATPase in the Golgi, regulates intracellular levels of the cadmium ion. FEMS microbiology letters 31 18510555
2005 Hailey-Hailey disease as an orthodisease of PMR1 deficiency in Saccharomyces cerevisiae. FEBS letters 31 15811312
2015 Wnt signaling regulates the stemness of lung cancer stem cells and its inhibitors exert anticancer effect on lung cancer SPC-A1 cells. Medical oncology (Northwood, London, England) 30 25731617
2012 Hailey-Hailey disease and tight junctions: Claudins 1 and 4 are regulated by ATP2C1 gene encoding Ca(2+) /Mn(2+) ATPase SPCA1 in cultured keratinocytes. Experimental dermatology 30 22639968
2007 Functional and immunocytochemical evidence for the expression and localization of the secretory pathway Ca2+-ATPase isoform 1 (SPCA1) in cerebellum relative to other Ca2+ pumps. Journal of neurochemistry 30 17680983
2003 Packing interactions between transmembrane helices alter ion selectivity of the yeast Golgi Ca2+/Mn2+-ATPase PMR1. The Journal of biological chemistry 30 12824173
2020 FAS/FAS-L-mediated apoptosis and autophagy of SPC-A-1 cells induced by water-soluble polysaccharide from Polygala tenuifolia. International journal of biological macromolecules 29 32027895
2004 Pmr1, a P-type ATPase, and Pdt1, an Nramp homologue, cooperatively regulate cell morphogenesis in fission yeast: the importance of Mn2+ homeostasis. Genes to cells : devoted to molecular & cellular mechanisms 29 14723709
2004 Anti-proliferative effects of oridonin on SPC-A-1 cells and its mechanism of action. The Journal of international medical research 28 15587755
2011 Impaired migration and cell volume regulation in aquaporin 5-deficient SPC-A1 cells. Respiratory physiology & neurobiology 27 21315850
2019 The protein kinase Cmk2 negatively regulates the calcium/calcineurin signalling pathway and expression of calcium pump genes PMR1 and PMC1 in budding yeast. Cell communication and signaling : CCS 26 30665402
2016 siRNA-induced TRAF6 knockdown promotes the apoptosis and inhibits the invasion of human lung cancer SPC-A1 cells. Oncology reports 26 26847475
2008 Activity and localization of the secretory pathway Ca2+-ATPase isoform 1 (SPCA1) in different areas of the mouse brain during postnatal development. Molecular and cellular neurosciences 25 18599310
2003 Four novel mutations in ATP2C1 found in Chinese patients with Hailey-Hailey disease. The British journal of dermatology 25 14510977
2018 Store-independent coupling between the Secretory Pathway Ca2+ transport ATPase SPCA1 and Orai1 in Golgi stress and Hailey-Hailey disease. Biochimica et biophysica acta. Molecular cell research 24 29555205
2015 Curcumol induces apoptosis in SPC-A-1 human lung adenocarcinoma cells and displays anti-neoplastic effects in tumor bearing mice. Asian Pacific journal of cancer prevention : APJCP 24 25824755
2010 Synergistic effects of tea polyphenols and ascorbic acid on human lung adenocarcinoma SPC-A-1 cells. Journal of Zhejiang University. Science. B 24 20506578
2008 Molecular and clinical characterization in Japanese and Korean patients with Hailey-Hailey disease: six new mutations in the ATP2C1 gene. Journal of dermatological science 24 18372165
2005 Caenorhabditis elegans PMR1, a P-type calcium ATPase, is important for calcium/manganese homeostasis and oxidative stress response. FEBS letters 24 15670846
2016 The loss of ATP2C1 impairs the DNA damage response and induces altered skin homeostasis: Consequences for epidermal biology in Hailey-Hailey disease. Scientific reports 23 27528123
2014 Loss of RhoA expression prevents proliferation and metastasis of SPCA1 lung cancer cells in vitro. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 25661383
2008 Apoptotic activity of genistein on human lung adenocarcinoma SPC-A-1 cells and preliminary exploration of its mechanisms using microarray. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 18295443
2004 Endonuclease-mediated mRNA decay requires tyrosine phosphorylation of polysomal ribonuclease 1 (PMR1) for the targeting and degradation of polyribosome-bound substrate mRNA. The Journal of biological chemistry 22 15375158
2017 RhoA inhibits apoptosis and increases proliferation of cultured SPCA1 lung cancer cells. Molecular medicine reports 21 28487954
2009 Acantholytic dermatosis of the crural folds with ATP2C1 mutation is a possible variant of Hailey-Hailey Disease. Journal of cutaneous medicine and surgery 21 19426624
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2014 The Ca(2+)/H(+) antiporter TMEM165 expression, localization in the developing, lactating and involuting mammary gland parallels the secretory pathway Ca(2+) ATPase (SPCA1). Biochemical and biophysical research communications 20 24530912
2001 Cloning of the Aspergillus niger pmrA gene, a homologue of yeast PMR1, and characterization of a pmrA null mutant. FEMS microbiology letters 20 11356574
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2009 KSRP-PMR1-exosome association determines parathyroid hormone mRNA levels and stability in transfected cells. BMC cell biology 18 19775426
1998 Molecular cloning of YlPMR1, a S. cerevisiae PMR1 homologue encoding a novel P-type secretory pathway Ca2+ -ATPase, in the yeast Yarrowia lipolytica. Gene 18 9461422
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2013 The secretory pathway calcium ATPase PMR-1/SPCA1 has essential roles in cell migration during Caenorhabditis elegans embryonic development. PLoS genetics 17 23696750
2007 Eight novel mutations of ATP2C1 identified in 17 Chinese families with Hailey-Hailey disease. Dermatology (Basel, Switzerland) 17 17911984
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2002 Ca(2+) signals in Pmr1-GFP-expressing COS-1 cells with functional endoplasmic reticulum. Biochemical and biophysical research communications 16 12051702
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2012 Bis(2-hydroxy-3-tert-butyl-5-methyl-phenyl)-methane (bis-phenol) is a potent and selective inhibitor of the secretory pathway Ca²⁺ ATPase (SPCA1). Biochemical and biophysical research communications 15 22796571
2010 Aquaporin 5 expression inhibited by LPS via p38/JNK signaling pathways in SPC-A1 cells. Respiratory physiology & neurobiology 15 20362698
2003 The role of hydrogen peroxide produced by polychlorinated biphenyls in PMR1-deficient yeast cells. Journal of biochemistry 15 12944380
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2009 Changes in expression and activity of the secretory pathway Ca2+ ATPase 1 (SPCA1) in A7r5 vascular smooth muscle cells cultured at different glucose concentrations. Bioscience reports 13 19527224
2002 Secretory expression and purification of Aspergillus niger glucose oxidase in Saccharomyces cerevisiae mutant deficient in PMR1 gene. Protein expression and purification 13 12182830
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