SPPL2A signal peptide peptidase like 2A [Homo sapiens (human)] - Gene

Summary

Official Symbol: SPPL2Aprovided by HGNC
Official Full Name: signal peptide peptidase like 2Aprovided by HGNC
Primary source: HGNC:HGNC:30227
See related: Ensembl:ENSG00000138600 MIM:608238; AllianceGenome:HGNC:30227
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: IMP3; PSL2; IMD86
Summary: 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]
Expression: Ubiquitous expression in colon (RPKM 15.8), duodenum (RPKM 10.9) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 15q21.2

Exon count:: 16

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	15	NC_000015.10 (50702266..50765706, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	15	NC_060939.1 (48509322..48573674, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	15	NC_000015.9 (50994463..51057903, complement)

Chromosome 15 - NC_000015.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

SPPL2a/b negatively regulates LOX-1 signaling and atherosclerosis.
Title: Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis.
inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of dendritic cells and impairing IFN-gamma production by mycobacterium-specific memory TH1* cells
Title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
Study propose that elements within the transmembrane segment and the luminal juxtamembrane domain facilitate intramembrane proteolysis of CD74 by SPPL2a.
Title: Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74.
In human B cells, SPPL2a is indispensable for turnover of CD74 N-terminal fragment. A human 15q21.2 microdeletion leads to loss of SPPL2a transcript and protein.
Title: Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells.
Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a).
Title: Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a).
Data show that endogenous SPPL2a - in agreement with overexpression studies - is localised in membranes of lysosomes/late endosomes.
Title: Signal-peptide-peptidase-like 2a (SPPL2a) is targeted to lysosomes/late endosomes by a tyrosine motif in its C-terminal tail.
SPPL2a and SPPL2b mediate the intramembrane cleavage, whereas neither SPP nor SPPL3 is capable of processing the Bri2 N-terminal fragment.
Title: Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b.
ADAM10 and SPPL2a were identified as two proteases implicated in FasL processing and release of the FasL intracellular domain, which has been shown to be important for retrograde FasL signaling
Title: The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells.
SPP, SPPL2a, -2b, -2c, and -3 probably cleave type II-oriented substrate peptides as shown by consensus analysis
Title: Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins.

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Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Immunodeficiency 86 MedGen: C5561995 OMIM: 619549 GeneReviews: Not available	not available

EBI GWAS Catalog

Description
Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. EBI GWAS Catalog EBI GWAS CatalogPubMed
Multiethnic meta-analysis of genome-wide association studies in &gt;100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

SPPL2A (e-PCR)
- UniSTS:503154

WI-11902 (e-PCR)
- UniSTS:20401

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables aspartic endopeptidase activity, intramembrane cleaving	IBA Inferred from Biological aspect of Ancestor more info
enables aspartic endopeptidase activity, intramembrane cleaving	IDA Inferred from Direct Assay more info	PubMed
enables aspartic endopeptidase activity, intramembrane cleaving	TAS Traceable Author Statement more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein homodimerization activity	IDA Inferred from Direct Assay more info	PubMed

Process	Evidence Code	Pubs
involved_in membrane protein ectodomain proteolysis	IDA Inferred from Direct Assay more info	PubMed
involved_in membrane protein intracellular domain proteolysis	IDA Inferred from Direct Assay more info	PubMed
involved_in membrane protein intracellular domain proteolysis	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in membrane protein proteolysis	IBA Inferred from Biological aspect of Ancestor more info
involved_in membrane protein proteolysis	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of immune response	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of immune response	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of tumor necrosis factor-mediated signaling pathway	TAS Traceable Author Statement more info

Component	Evidence Code	Pubs
is_active_in Golgi-associated vesicle membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in Golgi-associated vesicle membrane	IDA Inferred from Direct Assay more info	PubMed
is_active_in cytoplasmic side of endoplasmic reticulum membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in cytoplasmic side of endoplasmic reticulum membrane	IDA Inferred from Direct Assay more info	PubMed
located_in extracellular exosome	HDA more info	PubMed
located_in intracellular membrane-bounded organelle	IDA Inferred from Direct Assay more info
located_in late endosome	IDA Inferred from Direct Assay more info	PubMed
located_in late endosome membrane	IEA Inferred from Electronic Annotation more info
is_active_in lumenal side of endoplasmic reticulum membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in lumenal side of endoplasmic reticulum membrane	IDA Inferred from Direct Assay more info	PubMed
located_in lysosomal membrane	HDA more info	PubMed
is_active_in lysosomal membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in membrane	IDA Inferred from Direct Assay more info	PubMed
located_in plasma membrane	IDA Inferred from Direct Assay more info
located_in plasma membrane	TAS Traceable Author Statement more info

General protein information

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Preferred Names: signal peptide peptidase-like 2A

Names: IMP-3; SPP-like 2A; intramembrane cleaving protease; intramembrane protease 3; presenilin-like protein 2

NP_116191.2

EC 3.4.23.-

XP_005254779.1

EC 3.4.23.-

XP_016878169.1

EC 3.4.23.-

XP_016878170.1

EC 3.4.23.-

XP_054234976.1

EC 3.4.23.-

XP_054234977.1

EC 3.4.23.-

XP_054234978.1

EC 3.4.23.-

XP_054234979.1

EC 3.4.23.-

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

mRNA and Protein(s)

NM_032802.4 → NP_116191.2 signal peptide peptidase-like 2A precursor

See identical proteins and their annotated locations for NP_116191.2

Status: REVIEWED

Source sequence(s)

AA988423, AC012100, AK027446, AY169314

Consensus CDS

CCDS10138.1

UniProtKB/Swiss-Prot

B2RDS0, Q8TAW1, Q8TCT8, Q96SZ8

UniProtKB/TrEMBL

A0A8V8TN76

Related

ENSP00000261854.5, ENST00000261854.10

Conserved Domains (2) summary

cd02129
Location:41 → 160

PA_hSPPL_like; PA_hSPPL_like: Protease-associated domain containing human signal peptide peptidase-like (hSPPL)-like. This group contains various PA domain-containing proteins similar to hSPPL2a and 2b. These SPPLs are GxGD aspartic proteases. SPPL2a is sorted to the ...

pfam04258
Location:210 → 496

Peptidase_A22B; Signal peptide peptidase

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000015.10 Reference GRCh38.p14 Primary Assembly

Range

50702266..50765706 complement

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_017022681.2 → XP_016878170.1 signal peptide peptidase-like 2A isoform X3

UniProtKB/TrEMBL

A0A8V8TLY7, A0A8V8TLZ2

Related

ENSP00000513581.1, ENST00000698135.1
XM_017022680.2 → XP_016878169.1 signal peptide peptidase-like 2A isoform X2

UniProtKB/TrEMBL

A0A8V8TLY7
XM_005254722.4 → XP_005254779.1 signal peptide peptidase-like 2A isoform X1

UniProtKB/TrEMBL

A0A8V8TN76

Conserved Domains (2) summary

cd02129
Location:41 → 160

PA_hSPPL_like; PA_hSPPL_like: Protease-associated domain containing human signal peptide peptidase-like (hSPPL)-like. This group contains various PA domain-containing proteins similar to hSPPL2a and 2b. These SPPLs are GxGD aspartic proteases. SPPL2a is sorted to the ...

pfam04258
Location:210 → 514

Peptidase_A22B; Signal peptide peptidase

Alternate T2T-CHM13v2.0

Genomic

NC_060939.1 Alternate T2T-CHM13v2.0

Range

48509322..48573674 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054379002.1 → XP_054234977.1 signal peptide peptidase-like 2A isoform X4

UniProtKB/Swiss-Prot

B2RDS0, Q8TAW1, Q8TCT8, Q96SZ8

UniProtKB/TrEMBL

A0A8V8TN76
XM_054379001.1 → XP_054234976.1 signal peptide peptidase-like 2A isoform X1

UniProtKB/TrEMBL

A0A8V8TN76
XM_054379004.1 → XP_054234979.1 signal peptide peptidase-like 2A isoform X3

UniProtKB/TrEMBL

A0A8V8TLY7, A0A8V8TLZ2
XM_054379003.1 → XP_054234978.1 signal peptide peptidase-like 2A isoform X2

UniProtKB/TrEMBL

A0A8V8TLY7