SPCS3

gene
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Also known as FLJ22649SPC22/23SPC3YLR066WPRO3567

Summary

SPCS3 (signal peptidase complex subunit 3, HGNC:26212) is a protein-coding gene on chromosome 4q34.2, encoding Signal peptidase complex subunit 3 (P61009). Essential component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum. It is a common-essential gene (DepMap: required in 95.1% of cancer cell lines).

Involved in signal peptide processing and viral protein processing. Located in endoplasmic reticulum membrane. Part of signal peptidase complex.

Source: NCBI Gene 60559 — RefSeq curated summary.

At a glance

  • GWAS associations: 9
  • Clinical variants (ClinVar): 29 total — 2 pathogenic
  • Druggable target: yes
  • Cancer dependency (DepMap): dependent in 95.1% of screened cell lines (common-essential)
  • MANE Select transcript: NM_021928

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:26212
Approved symbolSPCS3
Namesignal peptidase complex subunit 3
Location4q34.2
Locus typegene with protein product
StatusApproved
AliasesFLJ22649, SPC22/23, SPC3, YLR066W, PRO3567
Ensembl geneENSG00000129128
Ensembl biotypeprotein_coding
OMIM618854
Entrez60559

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 retained_intron, 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000503362, ENST00000507001, ENST00000507678, ENST00000513139

RefSeq mRNA: 1 — MANE Select: NM_021928 NM_021928

CCDS: CCDS54823

Canonical transcript exons

ENST00000503362 — 5 exons

ExonStartEnd
ENSE00000886396176328198176332245
ENSE00002065140176319966176320219
ENSE00003524373176327162176327277
ENSE00003530109176322170176322243
ENSE00003600295176324181176324257

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 97.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 65.8625 / max 367.3419, expressed in 1823 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter IDTPM avgSamples expressed
5070065.38121823
507010.4813215

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
corpus epididymisUBERON:000435997.62gold quality
gingival epitheliumUBERON:000194997.61gold quality
pylorusUBERON:000116697.55gold quality
bone marrow cellCL:000209297.50gold quality
esophagus squamous epitheliumUBERON:000692097.48gold quality
deciduaUBERON:000245097.40gold quality
body of pancreasUBERON:000115097.37gold quality
renal glomerulusUBERON:000007497.15gold quality
gingivaUBERON:000182897.11gold quality
germinal epithelium of ovaryUBERON:000130497.10gold quality
monocyteCL:000057696.95gold quality
mononuclear cellCL:000084296.95gold quality
metanephric glomerulusUBERON:000473696.94gold quality
substantia nigra pars reticulataUBERON:000196696.87gold quality
squamous epitheliumUBERON:000691496.83gold quality
leukocyteCL:000073896.81gold quality
trabecular bone tissueUBERON:000248396.72gold quality
middle temporal gyrusUBERON:000277196.69gold quality
cardia of stomachUBERON:000116296.61gold quality
bone marrowUBERON:000237196.61gold quality
endometriumUBERON:000129596.60gold quality
parotid glandUBERON:000183196.50gold quality
Brodmann (1909) area 23UBERON:001355496.49gold quality
caput epididymisUBERON:000435896.48gold quality
upper leg skinUBERON:000426296.46gold quality
dorsal motor nucleus of vagus nerveUBERON:000287096.40gold quality
seminal vesicleUBERON:000099896.37gold quality
tracheaUBERON:000312696.33gold quality
buccal mucosa cellCL:000233696.29gold quality
tonsilUBERON:000237296.26gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 12.

ExperimentMarker?Max mean expression
E-CURD-88yes105.24
E-MTAB-9467yes67.08
E-HCAD-1yes63.15
E-HCAD-4yes60.60
E-CURD-46yes54.14
E-CURD-122yes49.79
E-MTAB-8410yes39.63
E-HCAD-11yes23.09
E-HCAD-9yes19.59
E-MTAB-10553yes10.70
E-HCAD-13yes7.01
E-CURD-112no3.03
E-ANND-3no0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

199 targeting SPCS3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-3163100.0077.238605
HSA-MIR-3613-3P100.0076.367965
HSA-MIR-3646100.0073.565283
HSA-MIR-30A-5P100.0076.313233
HSA-MIR-30B-5P100.0076.293248
HSA-MIR-30C-5P100.0076.293248
HSA-MIR-30D-5P100.0076.323233
HSA-MIR-30E-5P100.0076.323242
HSA-MIR-126-5P100.0072.713180
HSA-MIR-340-5P100.0072.504437
HSA-MIR-8485100.0077.574731
HSA-MIR-4682100.0068.891258
HSA-MIR-366299.9973.825684
HSA-MIR-428299.9975.366408
HSA-MIR-186-5P99.9970.833707
HSA-MIR-548C-3P99.9974.017587
HSA-MIR-607799.9968.042299
HSA-MIR-520D-5P99.9873.344883
HSA-MIR-524-5P99.9873.434882
HSA-MIR-1213699.9872.815713
HSA-MIR-4650-5P99.9864.69999
HSA-MIR-60799.9773.625593
HSA-MIR-1250-3P99.9670.044038
HSA-MIR-3605-5P99.9667.12932
HSA-MIR-551B-5P99.9671.283493
HSA-MIR-4725-3P99.9669.532520
HSA-MIR-6780B-5P99.9669.602562
HSA-MIR-568899.9673.234504
HSA-MIR-495-3P99.9672.814197
HSA-MIR-55999.9572.283609

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 95.1% of screened cell lines, common-essential.

Cross-species orthologs

8 orthologs

OrganismSymbolGene ID
danio_reriospcs3ENSDARG00000089976
mus_musculusArxes2ENSMUSG00000048040
mus_musculusArxes1ENSMUSG00000048355
mus_musculusSpcs3ENSMUSG00000054408
rattus_norvegicusSpcs3ENSRNOG00000038933
rattus_norvegicusENSRNOG00000078288
drosophila_melanogasterSpase22-23FBGN0039172
caenorhabditis_elegansWBGENE00019679

Protein

Protein identifiers

Signal peptidase complex subunit 3P61009 (reviewed: P61009)

Alternative names: Microsomal signal peptidase 22/23 kDa subunit

All UniProt accessions (1): P61009

UniProt curated annotations — full annotation on UniProt →

Function. Essential component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum. Essential for the SPC catalytic activity, possibly by stabilizing and positioning the active center of the complex close to the lumenal surface. (Microbial infection) Plays an important role in virion production of flaviviruses such as West Nile virus, Japanese enchephalitis virus, Dengue virus type 2 and Yellow Fever virus.

Subunit / interactions. Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3. Component of the signal peptidase complex paralog C (SPC-C) composed of a catalytic subunit SEC11C and three accessory subunits SPCS1, SPCS2 and SPCS3. Within the complex, interacts with SEC11A or SEC11C and SPCS1. The complex induces a local thinning of the ER membrane which is used to measure the length of the signal peptide (SP) h-region of protein substrates. This ensures the selectivity of the complex towards h-regions shorter than 18-20 amino acids.

Subcellular location. Endoplasmic reticulum membrane.

Similarity. Belongs to the SPCS3 family.

RefSeq proteins (1): NP_068747* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR007653SPC3Family

Pfam: PF04573

UniProt features (6 total): topological domain 2, chain 1, transmembrane region 1, glycosylation site 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDBMethodResolution (Å)
7P2PELECTRON MICROSCOPY4.9
7P2QELECTRON MICROSCOPY4.9

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-P61009-F191.720.83

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (1): 141

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

IDPathway
R-HSA-1799339SRP-dependent cotranslational protein targeting to membrane
R-HSA-381771Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)
R-HSA-400511Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)
R-HSA-422085Synthesis, secretion, and deacylation of Ghrelin
R-HSA-9768727Regulation of CDH1 posttranslational processing and trafficking to plasma membrane
R-HSA-9828806Maturation of hRSV A proteins
R-HSA-9918432Maturation of DENV proteins
R-HSA-1643685Disease
R-HSA-2980736Peptide hormone metabolism
R-HSA-392499Metabolism of proteins
R-HSA-400508Incretin synthesis, secretion, and inactivation
R-HSA-5663205Infectious disease
R-HSA-72766Translation
R-HSA-9820952Respiratory Syncytial Virus Infection Pathway
R-HSA-9820965Respiratory syncytial virus (RSV) genome replication, transcription and translation
R-HSA-9824446Viral Infection Pathways

MSigDB gene sets: 184 (showing top): RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_PROTEIN_TARGETING, chr4q34, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_PROTEIN_MATURATION, MORI_PLASMA_CELL_UP, WANG_RESPONSE_TO_FORSKOLIN_UP, IVANOVA_HEMATOPOIESIS_INTERMEDIATE_PROGENITOR, WANG_RESPONSE_TO_ANDROGEN_UP, WANG_PROSTATE_CANCER_ANDROGEN_INDEPENDENT, GOBP_SIGNAL_PEPTIDE_PROCESSING

GO Biological Process (4): obsolete signal peptide processing (GO:0006465), proteolysis (GO:0006508), viral protein processing (GO:0019082), protein targeting to ER (GO:0045047)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), signal peptidase complex (GO:0005787), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

CategoryPathways
Incretin synthesis, secretion, and inactivation2
Peptide hormone metabolism2
Metabolism of proteins2
Translation1
Regulation of CDH1 Expression and Function1
Respiratory syncytial virus (RSV) genome replication, transcription and translation1
Dengue Virus Genome Translation and Replication1
Disease1
Viral Infection Pathways1
Respiratory Syncytial Virus Infection Pathway1
Infectious disease1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
protein metabolic process1
viral process1
viral gene expression1
protein targeting1
establishment of protein localization to endoplasmic reticulum1
binding1
cytoplasm1
endomembrane system1
intracellular membrane-bounded organelle1
endoplasmic reticulum membrane1
membrane protein complex1
endoplasmic reticulum protein-containing complex1
serine-type endopeptidase complex1
organelle membrane1
nuclear outer membrane-endoplasmic reticulum membrane network1
endoplasmic reticulum subcompartment1
cellular anatomical structure1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

84 interactions, top by confidence:

ABTypeScore
SEC11CSPCS3psi-mi:“MI:0914”(association)0.820
SEC11CSPCS3psi-mi:“MI:0915”(physical association)0.820
SEC11ASPCS3psi-mi:“MI:0914”(association)0.770
SEC11ASPCS3psi-mi:“MI:0915”(physical association)0.770
GPC1HADHBpsi-mi:“MI:0914”(association)0.740
RAB6BGDI1psi-mi:“MI:0914”(association)0.730
CFTRESYT2psi-mi:“MI:2364”(proximity)0.710
ATXN1SPCS3psi-mi:“MI:0915”(physical association)0.670
STK4STRNpsi-mi:“MI:0914”(association)0.610
HTTSPCS3psi-mi:“MI:0915”(physical association)0.560
SEC11CAPOMpsi-mi:“MI:0914”(association)0.530
SPCS3ENTPD6psi-mi:“MI:0914”(association)0.530
SEC11ANPC1psi-mi:“MI:0914”(association)0.530
envPGRMC1psi-mi:“MI:0914”(association)0.460

BioGRID (166): SPCS3 (Proximity Label-MS), SPCS3 (Proximity Label-MS), SPCS3 (Proximity Label-MS), SPCS3 (Proximity Label-MS), SPCS3 (Proximity Label-MS), SPCS3 (Proximity Label-MS), SPCS3 (Proximity Label-MS), SPCS3 (Affinity Capture-MS), SPCS3 (Affinity Capture-MS), SPCS3 (Affinity Capture-MS), SPCS3 (Affinity Capture-MS), SPCS3 (Affinity Capture-RNA), SPCS3 (Affinity Capture-MS), SPCS3 (Affinity Capture-MS), SPCS3 (Affinity Capture-MS)

ESM2 similar proteins: A8WG88, C0HK79, C0HK80, E2RQ08, F1NNL1, F1PCT7, F1QR43, F4HTM3, F7B645, O18823, O96005, P04843, P04844, P07153, P0C152, P25235, P28687, P34525, P61008, P61009, P97259, Q08834, Q09328, Q3SZI6, Q3SZU5, Q4R4T0, Q4WGM4, Q53YF3, Q568Z4, Q5AYC8, Q5R9S8, Q5RBM1, Q5RFB6, Q5XIP9, Q60MW2, Q62186, Q6ZWQ7, Q8BR76, Q8BXQ2, Q8R4G6

Diamond homologs: B0G180, C0HK79, C0HK80, P28687, P34525, P61008, P61009, Q12133, Q3SZU5, Q53YF3, Q568Z4, Q60MW2, Q6BPD6, Q6C4R5, Q6ZWQ7, Q9LGB4, Q9MA96, Q9VCA9, Q10259, Q6CRY8

SIGNOR signaling

2 interactions.

AEffectBMechanism
SPCS3“form complex”“Signal peptidase complex, SEC11C variant”binding
SPCS3“form complex”“Signal peptidase complex, SEC11A variant”binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

PathwayPartnersFoldFDR
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane526.7×3e-04
Maturation of DENV proteins516.8×2e-03

GO biological processes:

GO termPartnersFoldFDR
cilium assembly77.2×7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

29 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic2
Likely pathogenic0
Uncertain significance14
Likely benign0
Benign0

Top pathogenic / likely-pathogenic (2)

Variant IDHGVSClassification
3062803GRCh37/hg19 4q32.1-35.2(chr4:161589441-190957473)x1Pathogenic
983279GRCh37/hg19 4q32.3-35.1(chr4:169108358-184425536)x1Pathogenic

SpliceAI

682 predictions. Top by Δscore:

VariantEffectΔscore
4:176320182:A:Tdonor_gain1.0000
4:176320217:GCT:Gdonor_gain1.0000
4:176320220:G:GGdonor_gain1.0000
4:176327232:A:Gdonor_gain1.0000
4:176327272:TCTC:Tdonor_gain1.0000
4:176327277:AGT:Adonor_loss1.0000
4:176327278:G:GCdonor_loss1.0000
4:176327278:G:GGdonor_gain1.0000
4:176327279:T:Gdonor_loss1.0000
4:176328302:A:Gdonor_gain1.0000
4:176328324:T:Gdonor_gain1.0000
4:176320216:TGCT:Tdonor_gain0.9900
4:176320217:GCTG:Gdonor_gain0.9900
4:176320218:CT:Cdonor_gain0.9900
4:176320220:GT:Gdonor_loss0.9900
4:176320223:A:ACdonor_loss0.9900
4:176320224:G:GGdonor_gain0.9900
4:176325840:TTC:Tdonor_gain0.9900
4:176327157:TATA:Tacceptor_loss0.9900
4:176327158:ATAGG:Aacceptor_loss0.9900
4:176327159:TA:Tacceptor_loss0.9900
4:176327160:A:AGacceptor_gain0.9900
4:176327160:AG:Aacceptor_gain0.9900
4:176327160:AGGC:Aacceptor_loss0.9900
4:176327161:G:GGacceptor_gain0.9900
4:176327161:G:GTacceptor_loss0.9900
4:176327161:GG:Gacceptor_gain0.9900
4:176327161:GGCT:Gacceptor_gain0.9900
4:176327273:CTCA:Cdonor_gain0.9900
4:176327280:GAG:Gdonor_loss0.9900

AlphaMissense

1171 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
4:176320125:A:CS17R0.999
4:176320127:C:AS17R0.999
4:176320127:C:GS17R0.999
4:176324219:T:CF86L0.999
4:176324221:T:AF86L0.999
4:176324221:T:GF86L0.999
4:176324201:T:AW80R0.998
4:176324201:T:CW80R0.998
4:176324206:T:AN81K0.998
4:176324206:T:GN81K0.998
4:176327183:T:AW106R0.998
4:176327183:T:CW106R0.998
4:176327187:A:CD107A0.998
4:176327187:A:TD107V0.998
4:176328229:T:AW148R0.998
4:176328229:T:CW148R0.998
4:176328251:G:AG155E0.998
4:176320114:C:AA13D0.997
4:176320134:G:CA20P0.997
4:176320141:T:CL22P0.997
4:176322216:G:AG64R0.997
4:176322216:G:CG64R0.997
4:176322217:G:AG64E0.997
4:176324234:G:CA91P0.997
4:176327178:T:AV104D0.997
4:176327186:G:CD107H0.997
4:176327246:T:CY127H0.997
4:176327274:T:AL136H0.997
4:176327274:T:CL136P0.997
4:176328248:C:AA154D0.997

dbSNP variants (sampled 300 via entrez): RS1000057830 (4:176331920 G>C), RS1000109788 (4:176331742 C>T), RS1000471587 (4:176319879 G>A,C,T), RS1000677858 (4:176318448 G>A), RS1000953710 (4:176324748 G>A), RS1001037646 (4:176330594 G>A), RS1001063750 (4:176330583 G>T), RS1001073879 (4:176330340 T>A,C), RS10013572 (4:176332270 A>C), RS1001386305 (4:176324461 GTTTGTTCTA>G), RS1001612335 (4:176331688 A>C,G), RS1001668696 (4:176319177 T>G), RS1001835496 (4:176318030 T>C), RS1001960493 (4:176325019 T>G), RS1002112796 (4:176325106 C>G,T)

Disease associations

OMIM: gene MIM:618854 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

StudyTraitp-value
GCST003989_18Chin dimples3.000000e-15
GCST004659_1Left ventricular mass1.000000e-07
GCST005988_4Serum albumin levels6.000000e-09
GCST005989_11Serum total protein levels4.000000e-09
GCST007354_1Intracranial aneurysm6.000000e-13
GCST010796_2093Electrocardiogram morphology (amplitude at temporal datapoints)7.000000e-09
GCST010796_2094Electrocardiogram morphology (amplitude at temporal datapoints)2.000000e-08
GCST010796_2095Electrocardiogram morphology (amplitude at temporal datapoints)4.000000e-08
GCST010796_2096Electrocardiogram morphology (amplitude at temporal datapoints)5.000000e-09

EFO canonical traits (2, from GWAS)

EFO IDTrait name
EFO:0008205left ventricular structural measurement
EFO:0004327electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066491 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

ChemicalActions (top 5)PubMed papers
Cyclosporineincreases expression4
Valproic Acidaffects expression, increases expression3
Phenylmercuric Acetateaffects cotreatment, increases expression2
Tobacco Smoke Pollutionincreases expression2
Tunicamycinincreases expression2
aristolochic acid Idecreases expression1
methylmercuric chlorideincreases expression1
triphenyl phosphateaffects expression1
bisphenol Aincreases expression1
pyrogallol 1,3-dimethyl etherdecreases expression, affects cotreatment1
beta-lapachoneincreases expression1
sodium arseniteincreases expression1
cobaltous chloridedecreases expression1
manganese chlorideincreases abundance, increases expression1
potassium chromate(VI)affects cotreatment, decreases expression1
cupric chlorideincreases expression1
epigallocatechin gallateaffects cotreatment, decreases expression1
perfluorooctane sulfonic aciddecreases expression1
CGP 52608affects binding, increases reaction1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideaffects cotreatment, increases expression1
ICG 001decreases expression1
abrinedecreases expression1
dorsomorphinaffects cotreatment, increases expression1
eprenetapoptaffects expression, affects reaction1
bisphenol Sincreases expression1
bisphenol AFincreases expression1
Benzo(a)pyreneincreases expression1
Cisplatindecreases expression1
Colforsinincreases expression1
Furaldehydeaffects cotreatment, increases expression1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL5652513BindingBinding affinity to human SPCS3 incubated for 45 mins by Kinobead based pull down assayNVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

CellosaurusNameCategorySex
CVCL_B2H5Abcam HeLa SPCS3 KOCancer cell lineFemale

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.

  • Disease cohort memberships (association, not causation — diseases whose associated-gene cohort lists this gene; a subset are also under Associated diseases): brain aneurysm