Presenilin-1 (PSEN1)
The protein contains 467 amino acids for an estimated molecular weight of 52668 Da.
Catalytic 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:15274632, PubMed:10545183, PubMed:10593990, PubMed:10206644, PubMed:10899933, PubMed:10811883, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874, PubMed:28269784, PubMed:20460383). Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). 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 (PubMed:9738936, PubMed:10593990, PubMed:10899933, PubMed:10811883). Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11953314). Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:9738936, PubMed:11953314). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similari (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.
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
Activation of MAPKK activity
Amyloid precursor protein catabolic process
Amyloid precursor protein metabolic process
Amyloid-beta formation
Amyloid-beta metabolic process
Astrocyte activation
Astrocyte activation involved in immune response
Autophagosome assembly
Blood vessel development
Brain morphogenesis
Cajal-Retzius cell differentiation
Calcium ion transmembrane transport
Calcium ion transport
Canonical Wnt signaling pathway
Cell fate specification
Cell-cell adhesion
Cellular response to amyloid-beta
Cellular response to DNA damage stimulus
Cerebellum development
Cerebral cortex cell migration
Choline transport
Dorsal/ventral neural tube patterning
Embryonic limb morphogenesis
Endoplasmic reticulum calcium ion homeostasis
Ephrin receptor signaling pathway
Epithelial cell proliferation
Extracellular matrix disassembly
Extracellular matrix organization
Heart looping
Hematopoietic progenitor cell differentiation
Intracellular signal transduction
L-glutamate import across plasma membrane
L-glutamate transmembrane transport
Learning or memory
Membrane protein ectodomain proteolysis
Membrane protein intracellular domain proteolysis
Memory
Mitochondrial transport
Modulation of age-related behavioral decline
Myeloid dendritic cell differentiation
Negative regulation of apoptotic process
Negative regulation of apoptotic signaling pathway
Negative regulation of axonogenesis
Negative regulation of core promoter binding
Negative regulation of epidermal growth factor-activated receptor activity
Negative regulation of gene expression
Negative regulation of neuron apoptotic process
Negative regulation of transcription by RNA polymerase II
Negative regulation of ubiquitin-dependent protein catabolic process
Negative regulation of ubiquitin-protein transferase activity
Neural retina development
Neuron apoptotic process
Neuron development
Neuron migration
Neuron projection maintenance
Neutrophil degranulation
Notch receptor processing
Notch receptor processing, ligand-dependent
Notch signaling pathway
Positive regulation of amyloid fibril formation
Positive regulation of apoptotic process
Positive regulation of catalytic activity
Positive regulation of coagulation
Positive regulation of dendritic spine development
Positive regulation of gene expression
Positive regulation of glycolytic process
Positive regulation of L-glutamate import across plasma membrane
Positive regulation of MAP kinase activity
Positive regulation of phosphorylation
Positive regulation of proteasomal ubiquitin-dependent protein catabolic process
Positive regulation of protein binding
Positive regulation of protein import into nucleus
Positive regulation of protein import into nucleus, translocation
Positive regulation of receptor recycling
Positive regulation of transcription, DNA-templated
Positive regulation of tumor necrosis factor biosynthetic process
Positive regulation of tumor necrosis factor production
Post-embryonic development
Protein glycosylation
Protein maturation
Protein processing
Protein transport
Regulation of canonical Wnt signaling pathway
Regulation of gene expression
Regulation of neuron projection development
Regulation of phosphorylation
Regulation of protein binding
Regulation of resting membrane potential
Regulation of synaptic plasticity
Regulation of synaptic transmission, glutamatergic
Response to oxidative stress
Sequestering of calcium ion
Single organismal cell-cell adhesion
Skeletal system morphogenesis
Skin morphogenesis
Smooth endoplasmic reticulum calcium ion homeostasis
Somitogenesis
Synapse organization
Synaptic vesicle targeting
T cell activation involved in immune response
T cell receptor signaling pathway
Thymus development
Cellular Component
Aggresome
Apical plasma membrane
Axon
Azurophil granule membrane
Cell cortex
Cell junction
Cell surface
Centrosome
Ciliary rootlet
Cytoplasmic vesicle
Dendritic shaft
Early endosome membrane
Endoplasmic reticulum
Endoplasmic reticulum membrane
Gamma-secretase complex
Golgi apparatus
Golgi membrane
Growth cone
Integral component of membrane
Integral component of plasma membrane
Integral component of presynaptic membrane
Kinetochore
Lysosomal membrane
Membrane
Membrane raft
Mitochondrial inner membrane
Mitochondrion
Neuromuscular junction
Neuron projection
Neuronal cell body
Nuclear membrane
Nuclear outer membrane
Nucleoplasm
Nucleus
Obsolete cell
Perinuclear region of cytoplasm
Plasma membrane
Presynapse
Protein complex
Protein-containing complex
Rough endoplasmic reticulum
Sarcolemma
Smooth endoplasmic reticulum
Synaptic vesicle
Z disc
The reference OMIM entry for this protein is 104311
Presenilin 1; psen1
Ps1
S182
DESCRIPTION
The PSEN1 gene encodes presenilin-1, which forms the catalytic component of gamma-secretase. Gamma-secretase is responsible for proteolytic cleavage of amyloid precursor protein (APP; 104760) and NOTCH receptor proteins (see 190198). Gamma-secretase is a multiprotein complex consisting of PSEN1 or its homolog PSEN2 (600759), nicastrin (605254), APH1 (see APH1A, 607629), and PEN2 (PSENEN; 607632) (summary by De Strooper, 2003; Chau et al., 2012).CLONING
By linkage mapping, Sherrington et al. (1995) defined a minimal cosegregating region containing the candidate gene for early-onset Alzheimer disease type 3 (607822), which had been linked to chromosome 14q24.3. Of 19 different transcripts isolated, 1 transcript, designated S182 by them, corresponded to a novel gene that encoded a 467-amino acid protein. Human and murine amino acid sequences shared 92% identity. Northern blot analysis identified a major 3-kb transcript expressed in most regions of the human brain and in several peripheral tissues. Structural analysis predicted an integral membrane protein with at least 7 transmembrane helical domains. The Alzheimer's Disease Collaborative Group (1995) isolated full-length cDNA clones for what they referred to as the PS1 gene. Contrary to previous mapping data, they found that the gene maps just telomeric to D14S77. The location at the 5-prime end of a specific YAC enabled them to determine that the gene is oriented 5-prime/3-prime centromere-telomere. Evidence for alternative splicing of the gene was found. Thinakaran et al. (1996) observed a polypeptide of approximately 43 kD in cells transfected with full-length human PS1 cDNA. Using 2 highly specific antibodies against nonoverlapping epitopes of presenilin-1, they demonstrated that the preponderant PS1-related species that accumulate in cultured mammalian cells and in the brains of rodents, primates, and humans are approximately 27-kD N-terminal and about 17-kD C-terminal derivatives. Epitope mapping analysis showed that PS1 cleavage occurred between amino acids 260 and 320. In brains of transgenic mice expressing human PS1, the 17-kD and the 27-kD PS1 derivatives accumulate to saturable levels, and at about 1:1 stoichiometry, independent of transgene-derived mRNA. The authors concluded that PS1 is subject to endoproteolytic processing in vivo. In a British familial Alzheimer disease (FAD) pedigree, a PS1 variant with a deletion of amino acids 290 to 319 (delE9) (104311.0012) was not cleaved. Rogaev et al. (1997) determined that alternative splicing produces several PSEN1 transcripts which encode distinct protein sequences; exon 9 is specifically removed from PSEN1 transcripts in leukocytes but not in most other tissues. PSEN1 transcripts are polyadenylated at 2 alternative sites. Mercken et al. (1996) produced 7 monoclonal antibodies that react with 3 nonoverlapping epitopes on the N-terminal hydrophilic tail of PS1. The monoclonal antibodies can detect the full-size 47-kD PS1 and the more abundant 28-kD degradation product in membrane extracts from human brain and human cell lines. PC12 cells transiently transfected with PS1 constructs containing 2 different Alzheimer mutations, M146V (104311.0007) and A246E (104311.0003), failed to generate the 28-kD degradation product in contrast to PC12 cells transfected with wildtype PS1. Mercken et al. (1996) suggested that type 3 Alzheimer disease may be the result of impaired proteolytic processing of PS1. La ... More on the omim web site
May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 22, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Dec. 9, 2018: 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
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 104311 was added.
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed