Gamma-secretase subunit PEN-2 (PSENEN)
The protein contains 101 amino acids for an estimated molecular weight of 12029 Da.
Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111). (updated: May 8, 2019)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt, is predicted to be membranous by TOPCONS.
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Biological Process
Amyloid fibril formation
Amyloid precursor protein catabolic process
Amyloid precursor protein metabolic process
Amyloid-beta formation
Apoptotic signaling pathway
Axon guidance
Cellular protein metabolic process
Ephrin receptor signaling pathway
Membrane protein ectodomain proteolysis
Membrane protein intracellular domain proteolysis
Neurotrophin TRK receptor signaling pathway
Notch receptor processing
Notch receptor processing, ligand-dependent
Notch signaling pathway
Positive regulation of apoptotic process
Positive regulation of catalytic activity
Positive regulation of endopeptidase activity
Protein processing
The reference OMIM entry for this protein is 607632
Presenilin enhancer 2, c. elegans, homolog of; psenen
Pen2
DESCRIPTION
PEN2 is a component of the gamma-secretase complex, which also includes presenilin (see PSEN1; 104311) and nicastrin (APH2; 605254). The gamma-secretase complex is required for the intramembrane proteolysis of a number of membrane proteins, including the amyloid-beta precursor protein (APP; 104760) and Notch (190198).CLONING
Francis et al. (2002) identified 2 presenilin enhancers in C. elegans, Aph1 (see APH1A; 607629) and Pen2. By searching sequence databases, they identified human, mouse, zebrafish, Drosophila, and Arabidopsis homologs of PEN2. The predicted 101-amino acid human PEN2 protein contains 2 transmembrane domains and shares 43% and 96% identity with C. elegans and mouse Pen2, respectively.BIOCHEMICAL FEATURES
- Crystal Structure The gamma-secretase complex, comprising presenilin (PSEN1; 104311), PEN2, APH1AL (see 607629), and nicastrin, is a membrane-embedded protease that controls a number of important cellular functions through substrate cleavage. Lu et al. (2014) reported the 3-dimensional structure of an intact human gamma-secretase complex at 4.5-angstrom resolution, determined by cryoelectron microscopy single-particle analysis. The gamma-secretase complex comprises a horseshoe-shaped transmembrane domain, which contains 19 transmembrane segments and a large extracellular domain from nicastrin, which sits immediately above the hollow space formed by the transmembrane horseshoe. The nicastrin extracellular domain is structurally similar to a large family of peptidases exemplified by the glutamate carboxypeptidase PSMA.MAPPING
By radiation hybrid analysis, Francis et al. (2002) mapped the PEN2 gene to chromosome 19. Didych et al. (2013) noted that the PSENEN and U2AF1L4 (601080) genes are in a head-to-head orientation on chromosome 19q13.12 with only 157 bp separating their first exons.GENE FUNCTION
By analyzing C. elegans mutant phenotypes, Francis et al. (2002) determined that Aph1 and Pen2 were required for Glp1/Notch-mediated signaling, both in embryonic patterning and in postembryonic germline proliferation. They observed that the human APH1 and PEN2 genes partially rescued the C. elegans mutant phenotypes, demonstrating conserved functions. Human APH1 and PEN2 had to be provided together to rescue the mutant phenotypes, and inclusion of PSEN1 improved rescue. Francis et al. (2002) concluded that APH1 and PEN2 cooperate closely in the same process to promote presenilin activity. Using RNA-mediated interference assays to inactivate Aph1, Pen2, or nicastrin in cultured Drosophila cells, Francis et al. (2002) observed reduction in gamma-secretase cleavage of beta-APP and Notch substrates and reduction in the levels of processed presenilin. They concluded that APH1 and PEN2 are required for Notch pathway signaling, gamma-secretase cleavage of beta-APP, and presenilin protein accumulation. In a commentary, Goutte (2002) discussed the contribution of Francis et al. (2002) to current understanding of how presenilins mediate the gamma-secretase cleavage of Notch transmembrane receptors and transmembrane beta-APP. Using coimmunoprecipitation experiments, Steiner et al. (2002) showed that PEN2 binds to nicastrin, PSEN1, and PSEN2 (600759), and they concluded that PEN2 is a critical component of PSEN1/gamma-secretase and PSEN2/gamma-secretase complexes. Steiner et al. (2002) observed that Pen2 levels were reduced in mice lacking Psen1 or both Psen1 and Pse ... More on the omim web site
May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 25, 2017: Additional information
No protein expression data in P. Mayeux work for PSENEN
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 607632 was added.
Feb. 25, 2016: Protein entry updated
Automatic update: model status changed
Feb. 24, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed