<p>An evidence describes the source of an annotation, e.g. an experiment that has been published in the scientific literature, an orthologous protein, a record from another database, etc.</p>
<p><a href="/manual/evidences">More...</a></p>
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<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>-Experimental evidence at protein leveli
<p>This indicates the type of evidence that supports the existence of the protein. Note that the ‘protein existence’ evidence does not give information on the accuracy or correctness of the sequence(s) displayed.<p><a href='/help/protein_existence' target='_top'>More...</a></p>
Select a section on the left to see content.
<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni
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). Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335). 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 similarity).By similarity
<p>Manually curated information which has been propagated from a related experimentally characterized protein.</p>
<p><a href="/manual/evidences#ECO:0000250">More...</a></p>
Manual assertion inferred from sequence similarity toi
<p>Manually curated information for which there is published experimental evidence.</p>
<p><a href="/manual/evidences#ECO:0000269">More...</a></p>
Manual assertion based on experiment ini
Cited for: PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320; 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN GAMMA-SECRETASE COMPLEX, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Sites
Feature key
Position(s)
DescriptionActions
Graphical view
Length
<p>This subsection of the ‘Function’ section is used for enzymes and indicates the residues directly involved in catalysis.<p><a href='/help/act_site' target='_top'>More...</a></p>Active sitei
<p>Manually curated information which has been inferred by a curator based on his/her scientific knowledge or on the scientific content of an article.</p>
<p><a href="/manual/evidences#ECO:0000305">More...</a></p>
Manual assertion inferred by curator fromi
Cited for: FUNCTION, ACTIVE SITES ASP-257 AND ASP-385, MUTAGENESIS OF TYR-256; ASP-257; ASP-385 AND TYR-389.
1
<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni
aspartic endopeptidase activity, intramembrane cleaving Source: UniProtKB
<p>Inferred from Direct Assay</p>
<p>Used to indicate a direct assay for the function, process or component indicated by the GO term.</p>
<p>More information in the <a href="http://geneontology.org/page/guide-go-evidence-codes#ida">GO evidence code guide</a></p>
Inferred from direct assayi
beta-catenin binding Source: UniProtKB
<p>Inferred from Physical Interaction</p>
<p>Covers physical interactions between the gene product of interest and another molecule (or ion, or complex).</p>
<p>More information in the <a href="http://geneontology.org/page/guide-go-evidence-codes#ipi">GO evidence code guide</a></p>
Inferred from physical interactioni
cadherin binding Source: GO_Central
<p>Inferred from Biological aspect of Ancestor</p>
<p>A type of phylogenetic evidence whereby an aspect of a descendent is inferred through the characterization of an aspect of a ancestral gene.</p>
<p>More information in the <a href="http://geneontology.org/page/guide-go-evidence-codes#iba">GO evidence code guide</a></p>
Inferred from biological aspect of ancestori
calcium channel activity Source: UniProtKB
<p>Inferred from Mutant Phenotype</p>
<p>Describes annotations that are concluded from looking at variations or changes in a gene product such as mutations or abnormal levels and includes techniques such as knockouts, overexpression, anti-sense experiments and use of specific protein inhibitors.</p>
<p>More information in the <a href="http://geneontology.org/page/guide-go-evidence-codes#imp">GO evidence code guide</a></p>
Inferred from mutant phenotypei
amyloid precursor protein catabolic process Source: HGNC
<p>Traceable Author Statement</p>
<p>Used for information from review articles where the original experiments are traceable through that article and also for information from text books or dictionaries.</p>
<p>More information in the <a href="http://geneontology.org/page/guide-go-evidence-codes#tas">GO evidence code guide</a></p>
Traceable author statementi
astrocyte activation Source: ARUK-UCL
<p>Inferred from Genetic Interaction</p>
<p>Used to describe “traditional” genetic interactions such as suppressors and synthetic lethals as well as other techniques such as functional complementation, rescue experiments, or inferences about a gene drawn from the phenotype of a mutation in a different gene.</p>
<p>More information in the <a href="http://geneontology.org/page/guide-go-evidence-codes#igi">GO evidence code guide</a></p>
Inferred from genetic interactioni
<p>UniProtKB Keywords constitute a <a href="http://www.uniprot.org/keywords">controlled vocabulary</a> with a hierarchical structure. Keywords summarise the content of a UniProtKB entry and facilitate the search for proteins of interest.<p><a href='/help/keywords' target='_top'>More...</a></p>Keywordsi
R-HSA-1251985 Nuclear signaling by ERBB4 R-HSA-1474228 Degradation of the extracellular matrix R-HSA-193692 Regulated proteolysis of p75NTR R-HSA-205043 NRIF signals cell death from the nucleus R-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus R-HSA-2644606 Constitutive Signaling by NOTCH1 PEST Domain Mutants R-HSA-2894862 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants R-HSA-2979096 NOTCH2 Activation and Transmission of Signal to the Nucleus R-HSA-3928665 EPH-ephrin mediated repulsion of cells R-HSA-6798695 Neutrophil degranulation R-HSA-9013507 NOTCH3 Activation and Transmission of Signal to the Nucleus R-HSA-9013700 NOTCH4 Activation and Transmission of Signal to the Nucleus R-HSA-9017802 Noncanonical activation of NOTCH3
SignaLink: a signaling pathway resource with multi-layered regulatory networks
1.A.54.1.1 the presenilin er ca(2+) leak channel (presenilin) family
<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides an exhaustive list of all names of the protein, from commonly used to obsolete, to allow unambiguous identification of a protein.<p><a href='/help/protein_names' target='_top'>More...</a></p>Protein namesi
Cited for: PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320; 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN GAMMA-SECRETASE COMPLEX, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section indicates the name(s) of the gene(s) that code for the protein sequence(s) described in the entry. Four distinct tokens exist: ‘Name’, ‘Synonyms’, ‘Ordered locus names’ and ‘ORF names’.<p><a href='/help/gene_name' target='_top'>More...</a></p>Gene namesi
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides information on the name(s) of the organism that is the source of the protein sequence.<p><a href='/help/organism-name' target='_top'>More...</a></p>Organismi
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section shows the unique identifier assigned by the NCBI to the source organism of the protein. This is known as the ‘taxonomic identifier’ or ‘taxid’.<p><a href='/help/taxonomic_identifier' target='_top'>More...</a></p>Taxonomic identifieri
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section contains the taxonomic hierarchical classification lineage of the source organism. It lists the nodes as they appear top-down in the taxonomic tree, with the more general grouping listed first.<p><a href='/help/taxonomic_lineage' target='_top'>More...</a></p>Taxonomic lineagei
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section is present for entries that are part of a <a href="http://www.uniprot.org/proteomes">proteome</a>, i.e. of a set of proteins thought to be expressed by organisms whose genomes have been completely sequenced.<p><a href='/help/proteomes_manual' target='_top'>More...</a></p>Proteomesi
UP000005640
<p>A UniProt <a href="http://www.uniprot.org/manual/proteomes_manual">proteome</a> can consist of several components. <br></br>The component name refers to the genomic component encoding a set of proteins.<p><a href='/help/proteome_component' target='_top'>More...</a></p> Componenti: Chromosome 14
<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi
Cited for: PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320; 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN GAMMA-SECRETASE COMPLEX, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320; 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN GAMMA-SECRETASE COMPLEX, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Note:Translocates with bound NOTCH1 from the endoplasmic reticulum and/or Golgi to the cell surface (PubMed:10593990). Colocalizes with CDH1/2 at sites of cell-cell contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the proximity of the plasma membrane (PubMed:9738936). Also present in azurophil granules of neutrophils (PubMed:11987239). Colocalizes with UBQLN1 in the cell membrane and in cytoplasmic juxtanuclear structures called aggresomes (PubMed:21143716).4 Publications
<p>This subsection of the <a href="http://www.uniprot.org/help/subcellular_location_section">'Subcellular location'</a> section describes the subcellular compartment where each non-membrane region of a membrane-spanning protein is found.<p><a href='/help/topo_dom' target='_top'>More...</a></p>Topological domaini
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
<p>This subsection of the <a href="http://www.uniprot.org/help/subcellular_location_section">'Subcellular location'</a> section describes the extent of a membrane-spanning region of the protein. It denotes the presence of both alpha-helical transmembrane regions and the membrane spanning regions of beta-barrel transmembrane proteins.<p><a href='/help/transmem' target='_top'>More...</a></p>Transmembranei
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi
<p>This subsection of the ‘Pathology and Biotech’ section provides information on the disease(s) associated with genetic variations in a given protein. The information is extracted from the scientific literature and diseases that are also described in the <a href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim">OMIM</a> database are represented with a <a href="http://www.uniprot.org/diseases">controlled vocabulary</a> in the following way:<p><a href='/help/involvement_in_disease' target='_top'>More...</a></p>Involvement in diseasei
Cited for: INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, CHARACTERIZATION OF VARIANTS AD3 VAL-79 AND LEU-82.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death.
<p>This subsection of the ‘Sequence’ section describes natural variant(s) of the protein sequence.<p><a href='/help/variant' target='_top'>More...</a></p>Natural variantiVAR_075260
Cited for: INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, CHARACTERIZATION OF VARIANTS AD3 VAL-79 AND LEU-82.
Cited for: INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, CHARACTERIZATION OF VARIANTS AD3 VAL-79 AND LEU-82.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
L → Fin AD3; no endoproteolytic cleavage; no APP nor NOTCH1 processing; no detectable amyloid-beta; almost abolishes gamma-secretase activity.3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of dementia characterized by pathologic finding of frontotemporal lobar degeneration, presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. In some cases, parkinsonian symptoms are prominent. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, amygdala. In most cases, protein tau deposits are found in glial cells and/or neurons.
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty.
<p>This subsection of the <a href="http://www.uniprot.org/manual/pathology_and_biotech_section">'Pathology and Biotech'</a> section describes the effect of the experimental mutation of one or more amino acid(s) on the biological properties of the protein.<p><a href='/help/mutagen' target='_top'>More...</a></p>Mutagenesisi
Cited for: INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, CHARACTERIZATION OF VARIANTS AD3 VAL-79 AND LEU-82.
Cited for: INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, CHARACTERIZATION OF VARIANTS AD3 VAL-79 AND LEU-82.
Cited for: INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, CHARACTERIZATION OF VARIANTS AD3 VAL-79 AND LEU-82.
Cited for: INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, CHARACTERIZATION OF VARIANTS AD3 VAL-79 AND LEU-82.
Cited for: INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, CHARACTERIZATION OF VARIANTS AD3 VAL-79 AND LEU-82.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
D → E: Abolishes gamma-secretase activity. Reduces production of amyloid-beta in APP processing. Accumulation of full-length PS1. Loss of binding of transition state analog gamma-secretase inhibitor.3 Publications
D → A: Loss of endoproteolytic cleavage. Reduces production of amyloid-beta in APP processing. Disassembly of the N-cadherin/PS1 complex at the cell surface. Impairs CDH2 processing.5 Publications
D → E: Abolishes gamma-secretase activity. Reduces production of amyloid-beta in APP processing. Accumulation of full-length PS1. Loss of binding of transition state analog gamma-secretase inhibitor.5 Publications
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANTS AD3 LEU-213 AND PHE-261, MUTAGENESIS OF ILE-202; LEU-226; PHE-237; LEU-248 AND LEU-424.
P → A: No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. Slightly increased amyloid-beta protein 42/40 ratio.1 Publication
P → G: Very little endoproteolysis. Little APP processing. No NOTCH1 processing. Very low levels amyloid-beta protein 40 and no detectable amyloid-beta protein 42.1 Publication
A → C: Some loss of endoproteolytic cleavage. Some loss of APP and NOTCH1 processing. Six-fold increase in amyloid-beta protein 42/40 ratio.1 Publication
L → A: No effect on endoproteolytic cleavage. No effect on APP processing. Impaired NOTCH1 processing. Greatly reduced amyloid-beta protein 42/40 ratio.1 Publication
L → G: Greatly reduced endoproteolytic cleavage. Very little APP and NOTCH1 processing. Very low levels of amyloid-beta protein 40 and no detectable amyloid-beta protein 42.1 Publication
L → V: No effect on endoproteolytic cleavage. No effect on APP processing. Impaired NOTCH1 processing. Some increase in amyloid-beta protein 42/40 ratio.1 Publication
<p>This subsection of the ‘PTM / Processing’ section describes the extent of a polypeptide chain in the mature protein following processing.<p><a href='/help/chain' target='_top'>More...</a></p>ChainiPRO_0000025591
<p>This subsection of the ‘PTM / Processing’ section specifies the position and type of each modified residue excluding <a href="http://www.uniprot.org/manual/lipid">lipids</a>, <a href="http://www.uniprot.org/manual/carbohyd">glycans</a> and <a href="http://www.uniprot.org/manual/crosslnk">protein cross-links</a>.<p><a href='/help/mod_res' target='_top'>More...</a></p>Modified residuei
<p>Manually validated information inferred from a combination of experimental and computational evidence.</p>
<p><a href="/manual/evidences#ECO:0000244">More...</a></p>
Manual assertion inferred from combination of experimental and computational evidencei
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
1
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM/processing</a> section describes post-translational modifications (PTMs). This subsection <strong>complements</strong> the information provided at the sequence level or describes modifications for which <strong>position-specific data is not yet available</strong>.<p><a href='/help/post-translational_modification' target='_top'>More...</a></p>Post-translational modificationi
Heterogeneous proteolytic processing generates N-terminal (NTF) and C-terminal (CTF) fragments of approximately 35 and 20 kDa, respectively. During apoptosis, the C-terminal fragment (CTF) is further cleaved by caspase-3 to produce the fragment, PS1-CTF12.4 Publications
Cited for: PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320; 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN GAMMA-SECRETASE COMPLEX, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION.
Cited for: FUNCTION, MUTAGENESIS OF MET-292, PROTEOLYTIC PROCESSING.
After endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-346 inhibits endoproteolysis.2 Publications
Cited for: PHOSPHORYLATION AT SER-310 AND SER-346, MUTAGENESIS OF SER-310 AND SER-346.
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<p>This subsection describes interesting single amino acid sites on the sequence that are not defined in any other subsection. This subsection can be displayed in different sections (‘Function’, ‘PTM / Processing’, ‘Pathology and Biotech’) according to its content.<p><a href='/help/site' target='_top'>More...</a></p>Sitei
<p>This section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms.<p><a href='/help/expression_section' target='_top'>More...</a></p>Expressioni
<p>This subsection of the ‘Expression’ section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms. By default, the information is derived from experiments at the mRNA level, unless specified ‘at protein level’. <br></br>Examples: <a href="http://www.uniprot.org/uniprot/P92958#expression">P92958</a>, <a href="http://www.uniprot.org/uniprot/Q8TDN4#expression">Q8TDN4</a>, <a href="http://www.uniprot.org/uniprot/O14734#expression">O14734</a><p><a href='/help/tissue_specificity' target='_top'>More...</a></p>Tissue specificityi
Detected in azurophile granules in neutrophils and in platelet cytoplasmic granules (at protein level) (PubMed:11987239). Expressed in a wide range of tissues including various regions of the brain, liver, spleen and lymph nodes (PubMed:7596406, PubMed:8641442, PubMed:8574969).4 Publications
