This gene encodes a member of the GXGD family of aspartic proteases, which are transmembrane proteins with two conserved catalytic motifs localized within the membrane-spanning regions, as well as a member of the signal peptide peptidase-like protease (SPPL) family. This protein is expressed in all major adult human tissues and localizes to late endosomal compartments and lysos... See more...

Aliases for SPPL2A Gene

Aliases for SPPL2A Gene

  • Signal Peptide Peptidase Like 2A 2 3 5
  • Presenilin-Like Protein 2 2 3 4
  • Intramembrane Protease 3 2 3 4
  • Signal Peptide Peptidase-Like 2A 3 4
  • SPP-Like 2A 3 4
  • IMP-3 3 4
  • IMP3 3 4
  • PSL2 3 4
  • Intramembrane Cleaving Protease 3
  • EC 3.4.23.- 4
  • SPPL2a 4

External Ids for SPPL2A Gene

Previous GeneCards Identifiers for SPPL2A Gene

  • GC15M046557
  • GC15M044045
  • GC15M048578
  • GC15M048715
  • GC15M048787
  • GC15M050999
  • GC15M027830

Summaries for SPPL2A Gene

Entrez Gene Summary for SPPL2A Gene

  • This gene encodes a member of the GXGD family of aspartic proteases, which are transmembrane proteins with two conserved catalytic motifs localized within the membrane-spanning regions, as well as a member of the signal peptide peptidase-like protease (SPPL) family. This protein is expressed in all major adult human tissues and localizes to late endosomal compartments and lysosomal membranes. A pseudogene of this gene also lies on chromosome 15. [provided by RefSeq, Feb 2012]

GeneCards Summary for SPPL2A Gene

SPPL2A (Signal Peptide Peptidase Like 2A) is a Protein Coding gene. Diseases associated with SPPL2A include Cerebral Amyloid Angiopathy, Itm2b-Related, 1 and Cerebral Amyloid Angiopathy, Itm2b-Related, 2. Among its related pathways are TNF signaling (REACTOME) and Signaling by GPCR. Gene Ontology (GO) annotations related to this gene include protein homodimerization activity and aspartic-type endopeptidase activity. An important paralog of this gene is SPPL2B.

UniProtKB/Swiss-Prot Summary for SPPL2A Gene

  • Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Functions in FASLG, ITM2B and TNF processing (PubMed:16829952, PubMed:16829951, PubMed:17557115, PubMed:17965014). Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF-alpha (TNF), which promotes the release of the intracellular domain (ICD) for signaling to the nucleus (PubMed:16829952). Also responsible for the intramembrane cleavage of Fas antigen ligand FASLG, which promotes the release of the intracellular FasL domain (FasL ICD) (PubMed:17557115). May play a role in the regulation of innate and adaptive immunity (PubMed:16829952). Catalyzes the intramembrane cleavage of the simian foamy virus envelope glycoprotein gp130 independently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis (PubMed:23132852).

Gene Wiki entry for SPPL2A Gene

Additional gene information for SPPL2A Gene

No data available for CIViC Summary , Tocris Summary , PharmGKB "VIP" Summary , Rfam classification and piRNA Summary for SPPL2A Gene

Genomics for SPPL2A Gene

GeneHancer (GH) Regulatory Elements for SPPL2A Gene

Promoters and enhancers for SPPL2A Gene
- Elite GeneHancer and/or Elite GeneHancer-gene association Download GeneHancer data from 2017 publication | Request up-to-date GeneHancer data (full dataset)

GeneHancers around SPPL2A on UCSC Golden Path with GeneCards custom track

Cistromic (ChIP-Seq) regulation report from SPP (The Signaling Pathways Project) for SPPL2A

Top Transcription factor binding sites by QIAGEN in the SPPL2A gene promoter:
  • aMEF-2
  • E47
  • Elk-1
  • Evi-1
  • GR
  • GR-alpha
  • MEF-2A
  • POU2F1
  • POU2F1a
  • RSRFC4

Genomic Locations for SPPL2A Gene

Genomic Locations for SPPL2A Gene
chr15:50,702,266-50,766,158
(GRCh38/hg38)
Size:
63,893 bases
Orientation:
Minus strand
chr15:50,999,506-51,058,005
(GRCh37/hg19)
Size:
58,500 bases
Orientation:
Minus strand

Genomic View for SPPL2A Gene

Genes around SPPL2A on UCSC Golden Path with GeneCards custom track

Cytogenetic band:
SPPL2A Gene in genomic location: bands according to Ensembl, locations according to GeneLoc (and/or Entrez Gene and/or Ensembl if different)
Genomic Location for SPPL2A Gene
GeneLoc Logo Genomic Neighborhood Exon StructureGene Density

RefSeq DNA sequence for SPPL2A Gene

Proteins for SPPL2A Gene

  • Protein details for SPPL2A Gene (UniProtKB/Swiss-Prot)

    Protein Symbol:
    Q8TCT8-SPP2A_HUMAN
    Recommended name:
    Signal peptide peptidase-like 2A
    Protein Accession:
    Q8TCT8
    Secondary Accessions:
    • B2RDS0
    • Q8TAW1
    • Q96SZ8

    Protein attributes for SPPL2A Gene

    Size:
    520 amino acids
    Molecular mass:
    58143 Da
    Quaternary structure:
    • Interacts with ITM2B (PubMed:17965014).
    SequenceCaution:
    • Sequence=BAB55117.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=CAD13133.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};

neXtProt entry for SPPL2A Gene

Post-translational modifications for SPPL2A Gene

  • Glycosylated.
  • Glycosylation at Asn58, Asn66, Asn74, Asn116, Asn126, Asn149, and Asn155
  • Modification sites at PhosphoSitePlus
  • Glycosylation from GlyConnect
    • SPP2A_HUMAN (1746)

Other Protein References for SPPL2A Gene

Antibody Products

  • Abcam antibodies for SPPL2A
  • Santa Cruz Biotechnology (SCBT) Antibodies for SPPL2A

No data available for DME Specific Peptides for SPPL2A Gene

Domains & Families for SPPL2A Gene

Gene Families for SPPL2A Gene

Human Protein Atlas (HPA):
  • Enzymes
  • Plasma proteins
  • Predicted membrane proteins
  • Transporters

Protein Domains for SPPL2A Gene

Blocks:
  • Protease-associated PA
InterPro:
ProtoNet:

Suggested Antigen Peptide Sequences for SPPL2A Gene

GenScript: Design optimal peptide antigens:
  • Presenilin-like protein 2 (PSL2_HUMAN)

Graphical View of Domain Structure for InterPro Entry

Q8TCT8

UniProtKB/Swiss-Prot:

SPP2A_HUMAN :
  • The PAL motif is required for normal active site conformation. The catalytic domains embedded in the membrane are in the opposite orientation to that of the presenilin protein family; therefore, it is predicted to cleave type II-oriented substrate peptides like the prototypic protease SPP. The C-terminal tail is necessary for lysosomal transport.
  • Belongs to the peptidase A22B family.
Domain:
  • The PAL motif is required for normal active site conformation. The catalytic domains embedded in the membrane are in the opposite orientation to that of the presenilin protein family; therefore, it is predicted to cleave type II-oriented substrate peptides like the prototypic protease SPP. The C-terminal tail is necessary for lysosomal transport.
Family:
  • Belongs to the peptidase A22B family.
genes like me logo Genes that share domains with SPPL2A: view

Function for SPPL2A Gene

Molecular function for SPPL2A Gene

UniProtKB/Swiss-Prot Function:
Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Functions in FASLG, ITM2B and TNF processing (PubMed:16829952, PubMed:16829951, PubMed:17557115, PubMed:17965014). Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF-alpha (TNF), which promotes the release of the intracellular domain (ICD) for signaling to the nucleus (PubMed:16829952). Also responsible for the intramembrane cleavage of Fas antigen ligand FASLG, which promotes the release of the intracellular FasL domain (FasL ICD) (PubMed:17557115). May play a role in the regulation of innate and adaptive immunity (PubMed:16829952). Catalyzes the intramembrane cleavage of the simian foamy virus envelope glycoprotein gp130 independently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis (PubMed:23132852).

Enzyme Numbers (IUBMB) for SPPL2A Gene

Phenotypes From GWAS Catalog for SPPL2A Gene

Gene Ontology (GO) - Molecular Function for SPPL2A Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005515 protein binding IPI 16189514
GO:0008233 peptidase activity IEA --
GO:0016787 hydrolase activity IEA --
GO:0042500 aspartic endopeptidase activity, intramembrane cleaving IEA,IDA 2313285
GO:0042803 protein homodimerization activity IDA 15385547
genes like me logo Genes that share ontologies with SPPL2A: view
genes like me logo Genes that share phenotypes with SPPL2A: view

Animal Models for SPPL2A Gene

MGI Knock Outs for SPPL2A:

Animal Model Products

miRNA for SPPL2A Gene

miRTarBase miRNAs that target SPPL2A

Clone Products

No data available for Human Phenotype Ontology , Transcription Factor Targets and HOMER Transcription for SPPL2A Gene

Localization for SPPL2A Gene

Subcellular locations from UniProtKB/Swiss-Prot for SPPL2A Gene

Late endosome membrane; Multi-pass membrane protein. Lysosome membrane; Multi-pass membrane protein. Membrane; Multi-pass membrane protein; Lumenal side. Note=Colocalizes with palmitoylated and myristoylated proteins at the plasma membrane.

Subcellular locations from

COMPARTMENTS
Extracellular space Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi Apparatus Nucleus Mitochondrion 0 1 2 3 4 5 Confidence
COMPARTMENTS Subcellular localization image for SPPL2A gene
Compartment Confidence
plasma membrane 5
endoplasmic reticulum 5
endosome 5
lysosome 2
extracellular 1
cytoskeleton 1
nucleus 1
cytosol 1
golgi apparatus 1

Subcellular locations from the

Human Protein Atlas (HPA)

Gene Ontology (GO) - Cellular Components for SPPL2A Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005764 lysosome IEA --
GO:0005765 lysosomal membrane IBA 21873635
GO:0005768 endosome IEA --
GO:0005770 late endosome IDA 16829952
GO:0005886 plasma membrane TAS,IDA --
genes like me logo Genes that share ontologies with SPPL2A: view

Pathways & Interactions for SPPL2A Gene

PathCards logo

SuperPathways for SPPL2A Gene

genes like me logo Genes that share pathways with SPPL2A: view

Pathways by source for SPPL2A Gene

Gene Ontology (GO) - Biological Process for SPPL2A Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0006508 proteolysis IEA --
GO:0006509 membrane protein ectodomain proteolysis IDA 16829951
GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway TAS --
GO:0031293 membrane protein intracellular domain proteolysis IMP,IEA 16829952
GO:0033619 membrane protein proteolysis IDA,IBA 2313285
genes like me logo Genes that share ontologies with SPPL2A: view

No data available for SIGNOR curated interactions for SPPL2A Gene

Drugs & Compounds for SPPL2A Gene

No Compound Related Data Available

Transcripts for SPPL2A Gene

mRNA/cDNA for SPPL2A Gene

1 REFSEQ mRNAs :
9 NCBI additional mRNA sequence :
7 Ensembl transcripts including schematic representations, and UCSC links to gene/alias where relevant :

Clone Products

Alternative Splicing Database (ASD) splice patterns (SP) for SPPL2A Gene

ExUns: 1 ^ 2 ^ 3 ^ 4a · 4b ^ 5 ^ 6 ^ 7 ^ 8 ^ 9 ^ 10 ^ 11 ^ 12 ^ 13a · 13b · 13c ^ 14 ^ 15a · 15b ^ 16 ^ 17
SP1: - - - -
SP2:
SP3:
SP4:

Relevant External Links for SPPL2A Gene

GeneLoc Exon Structure for
SPPL2A

Expression for SPPL2A Gene

mRNA expression in normal human tissues from GTEx, Illumina, BioGPS, and SAGE for SPPL2A Gene

mRNA expression in embryonic tissues and stem cells from LifeMap Discovery

mRNA differential expression in normal tissues according to GTEx for SPPL2A Gene

This gene is overexpressed in Muscle - Skeletal (x4.8).

Protein differential expression in normal tissues from HIPED for SPPL2A Gene

This gene is overexpressed in Nasal epithelium (42.6), Serum (8.8), and Monocytes (7.1).

Integrated Proteomics: protein expression in normal tissues and cell lines from ProteomicsDB, MaxQB, and MOPED for SPPL2A Gene



Transcriptomic regulation report from SPP (The Signaling Pathways Project) for SPPL2A

SOURCE GeneReport for Unigene cluster for SPPL2A Gene:

Hs.401537

mRNA Expression by UniProt/SwissProt for SPPL2A Gene:

Q8TCT8-SPP2A_HUMAN
Tissue specificity: Ubiquitous.

Evidence on tissue expression from TISSUES for SPPL2A Gene

  • Blood(4.3)
  • Pancreas(4.3)
  • Lymph node(2.3)
  • Spleen(2.3)
genes like me logo Genes that share expression patterns with SPPL2A: view

No data available for Protein tissue co-expression partners and Phenotype-based relationships between genes and organs from Gene ORGANizer for SPPL2A Gene

Orthologs for SPPL2A Gene

This gene was present in the common ancestor of eukaryotes.

Orthologs for SPPL2A Gene

Organism Taxonomy Gene Similarity Type Details
chimpanzee
(Pan troglodytes)
Mammalia SPPL2A 31 30
  • 99.74 (n)
OneToOne
cow
(Bos Taurus)
Mammalia SPPL2A 31 30
  • 93.23 (n)
OneToOne
dog
(Canis familiaris)
Mammalia SPPL2A 31 30
  • 92.05 (n)
OneToOne
rat
(Rattus norvegicus)
Mammalia Sppl2a 30
  • 83.94 (n)
mouse
(Mus musculus)
Mammalia Sppl2a 17 31 30
  • 83.75 (n)
oppossum
(Monodelphis domestica)
Mammalia SPPL2A 31
  • 73 (a)
OneToOne
platypus
(Ornithorhynchus anatinus)
Mammalia SPPL2A 31
  • 69 (a)
OneToOne
chicken
(Gallus gallus)
Aves SPPL2A 31 30
  • 74.37 (n)
OneToOne
lizard
(Anolis carolinensis)
Reptilia SPPL2A 31
  • 53 (a)
OneToOne
tropical clawed frog
(Silurana tropicalis)
Amphibia sppl2a 30
  • 65.36 (n)
zebrafish
(Danio rerio)
Actinopterygii zgc:123258 30
  • 55.67 (n)
worm
(Caenorhabditis elegans)
Secernentea imp-1 31 30
  • 48.54 (n)
OneToMany
C36B1.12 32
  • 28 (a)
baker's yeast
(Saccharomyces cerevisiae)
Saccharomycetes -- 31
  • 16 (a)
OneToMany
rice
(Oryza sativa)
Liliopsida Os11g0433200 30
  • 48.02 (n)
Species where no ortholog for SPPL2A was found in the sources mined by GeneCards:
  • A. gosspyii yeast (Ashbya gossypii)
  • Actinobacteria (Mycobacterium tuberculosis)
  • African clawed frog (Xenopus laevis)
  • African malaria mosquito (Anopheles gambiae)
  • Alicante grape (Vitis vinifera)
  • alpha proteobacteria (Wolbachia pipientis)
  • amoeba (Dictyostelium discoideum)
  • Archea (Pyrococcus horikoshii)
  • barley (Hordeum vulgare)
  • beta proteobacteria (Neisseria meningitidis)
  • bread mold (Neurospora crassa)
  • Chromalveolata (Phytophthora infestans)
  • common water flea (Daphnia pulex)
  • corn (Zea mays)
  • E. coli (Escherichia coli)
  • filamentous fungi (Aspergillus nidulans)
  • Firmicute bacteria (Streptococcus pneumoniae)
  • fission yeast (Schizosaccharomyces pombe)
  • fruit fly (Drosophila melanogaster)
  • green algae (Chlamydomonas reinhardtii)
  • honey bee (Apis mellifera)
  • K. lactis yeast (Kluyveromyces lactis)
  • loblloly pine (Pinus taeda)
  • malaria parasite (Plasmodium falciparum)
  • medicago trunc (Medicago Truncatula)
  • moss (Physcomitrella patens)
  • orangutan (Pongo pygmaeus)
  • pig (Sus scrofa)
  • rainbow trout (Oncorhynchus mykiss)
  • rice blast fungus (Magnaporthe grisea)
  • schistosome parasite (Schistosoma mansoni)
  • sea anemone (Nematostella vectensis)
  • sea squirt (Ciona intestinalis)
  • sea squirt (Ciona savignyi)
  • sea urchin (Strongylocentrotus purpuratus)
  • sorghum (Sorghum bicolor)
  • soybean (Glycine max)
  • stem rust fungus (Puccinia graminis)
  • sugarcane (Saccharum officinarum)
  • thale cress (Arabidopsis thaliana)
  • tomato (Lycopersicon esculentum)
  • toxoplasmosis (Toxoplasma gondii)
  • Trichoplax (Trichoplax adhaerens)
  • wheat (Triticum aestivum)

Evolution for SPPL2A Gene

ENSEMBL:
Gene Tree for SPPL2A (if available)
TreeFam:
Gene Tree for SPPL2A (if available)
Aminode:
Evolutionary constrained regions (ECRs) for SPPL2A: view image

Paralogs for SPPL2A Gene

Paralogs for SPPL2A Gene

(2) SIMAP similar genes for SPPL2A Gene using alignment to 3 proteins:

  • SPP2A_HUMAN
  • H0YNA2_HUMAN
  • H0YNA7_HUMAN

Pseudogenes.org Pseudogenes for SPPL2A Gene

genes like me logo Genes that share paralogs with SPPL2A: view

Variants for SPPL2A Gene

Sequence variations, with clinical significance, from ClinVar and Humsavar, with links to dbSNP for SPPL2A Gene

SNP ID Clinical significance and condition Chr 15 pos Variation AA Info Type
rs8034443 - p.Val90Ile

Additional dbSNP identifiers (rs#s) for SPPL2A Gene

Structural Variations from Database of Genomic Variants (DGV) for SPPL2A Gene

Variant ID Type Subtype PubMed ID
dgv2594n100 CNV gain 25217958
dgv317n27 CNV gain 19166990
dgv4525n54 CNV gain 21841781
dgv4526n54 CNV gain 21841781
esv2609237 CNV deletion 19546169
esv2659888 CNV deletion 23128226
esv3636449 CNV loss 21293372
nsv1043273 CNV loss 25217958
nsv1044320 CNV loss 25217958
nsv1047443 CNV gain 25217958
nsv1051400 CNV gain 25217958
nsv457137 CNV loss 19166990
nsv471242 CNV gain 18288195
nsv569398 CNV loss 21841781
nsv569402 CNV loss 21841781

Variation tolerance for SPPL2A Gene

Residual Variation Intolerance Score: 76% of all genes are more intolerant (likely to be disease-causing)
Gene Damage Index Score: 4.01; 60.26% of all genes are more intolerant (likely to be disease-causing)

Additional Variant Information for SPPL2A Gene

SNPedia medical, phenotypic, and genealogical associations of SNPs for
SPPL2A

No data available for Polymorphic Variants from UniProtKB/Swiss-Prot for SPPL2A Gene

Disorders for SPPL2A Gene

MalaCards: The human disease database

(2) MalaCards diseases for SPPL2A Gene - From: DISEASES

Disorder Aliases PubMed IDs
cerebral amyloid angiopathy, itm2b-related, 1
  • dementia, familial british; fbd
cerebral amyloid angiopathy, itm2b-related, 2
  • dementia, familial danish; fdd
- elite association - COSMIC cancer census association via MalaCards

Additional Disease Information for SPPL2A

genes like me logo Genes that share disorders with SPPL2A: view

No data available for UniProtKB/Swiss-Prot and Genatlas for SPPL2A Gene

Publications for SPPL2A Gene

  1. Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b. (PMID: 17965014) Martin L … Haass C (The Journal of biological chemistry 2008) 3 4 23 54
  2. The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells. (PMID: 17557115) Kirkin V … Zörnig M (Cell death and differentiation 2007) 3 4 23 54
  3. Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins. (PMID: 15385547) Friedmann E … Martoglio B (The Journal of biological chemistry 2004) 3 4 23 54
  4. Identification of signal peptide peptidase, a presenilin-type aspartic protease. (PMID: 12077416) Weihofen A … Martoglio B (Science (New York, N.Y.) 2002) 2 3 4 54
  5. Novel class of polytopic proteins with domains associated with putative protease activity. (PMID: 12139484) Grigorenko AP … Rogaev EI (Biochemistry. Biokhimiia 2002) 2 3 4 54

Products for SPPL2A Gene

Sources for SPPL2A Gene