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Presenilin-1 (PS-1; STM-1; E5-1; AD) Ca2+ leak channel (part of the γ-secretase complex; expression alters the lipid raft composition in neuronal membranes (Eckert and Müller, 2009)). The first 5 TMSs of presenilin-1 are homologous to the 5 TMS CD47 antigenic protein, a constituent of the osteoclast fusion complex (1.N.1.1.1), and CD47 is therefore a presenilin homologue (unpublished observations).  The active site of gamma-secretase resides in an aqueous catalytic pore within the lipid bilayer and is tapered around the catalytic aspartates (Sato et al. 2006). TMS 6 and TMS 7 contribute to the hydrophilic pore. Residues at the luminal portion of TMS 6 are predicted to form a subsite for substrate or inhibitor binding on the α-helix facing the hydrophilic milieu, whereas those around the GxGD catalytic motif within TMS 7 are water accessible (Sato et al. 2006).

Accession Number:P49768
Protein Name:Presenilin-1 aka Protein S182
Molecular Weight:52668.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:9
Location1 / Topology2 / Orientation3: Endoplasmic reticulum membrane1 / Multi-pass membrane protein2
Substrate peptides, inorganic cations, Ca2+

Cross database links:

Genevestigator: P49768
eggNOG: prNOG04687
DIP: DIP-1134N
RefSeq: NP_000012.1    NP_015557.2   
Entrez Gene ID: 5663   
Pfam: PF01080   
OMIM: 104311  gene
600274  phenotype
607822  phenotype
KEGG: hsa:5663   

Gene Ontology

GO:0009986 C:cell surface
GO:0005789 C:endoplasmic reticulum membrane
GO:0000139 C:Golgi membrane
GO:0005639 C:integral to nuclear inner membrane
GO:0005887 C:integral to plasma membrane
GO:0000776 C:kinetochore
GO:0005640 C:nuclear outer membrane
GO:0008013 F:beta-catenin binding
GO:0030165 F:PDZ domain binding
GO:0042987 P:amyloid precursor protein catabolic process
GO:0006916 P:anti-apoptosis
GO:0016337 P:cell-cell adhesion
GO:0007059 P:chromosome segregation
GO:0008624 P:induction of apoptosis by extracellular sig...
GO:0006509 P:membrane protein ectodomain proteolysis
GO:0031293 P:membrane protein intracellular domain prote...
GO:0007220 P:Notch receptor processing

References (74)

[1] “Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.”  Sherrington   7596406
[2] “Identification and characterization of presenilin I-467, I-463 and I-374.”  Sahara   8641442
[3] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota   14702039
[4] “The DNA sequence and analysis of human chromosome 14.”  Heilig   12508121
[5] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project   15489334
[6] “Cloning of Xenopus presenilin-alpha and -beta cDNAs and their differential expression in oogenesis and embryogenesis.”  Tsujimura   9070286
[7] “Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes. Identification of a novel splice variant.”  Vidal   8804415
[8] “Purification and characterization of the human gamma-secretase complex.”  Fraering   15274632
[9] “Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells.”  Kovacs   8574969
[10] “Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue.”  Podlisny   9173929
[11] “Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C.”  Walter   9144240
[12] “Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa C-terminal fragment are death substrates for proteases of the caspase family.”  Gruenberg   9485372
[13] “Direct association of presenilin-1 with beta-catenin.”  Murayama   9738936
[14] “Interaction of presenilins with the filamin family of actin-binding proteins.”  Zhang   9437013
[15] “Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis.”  Steiner   10545183
[16] “Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting with the C terminus of presenilin-1.”  Xu   10551805
[17] “Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch.”  Ray   10593990
[18] “Presenilins interact with armadillo proteins including neural-specific plakophilin-related protein and beta-catenin.”  Levesque   10037471
[19] “Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts.”  Georgakopoulos   10635315
[20] “Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.”  Wolfe   10206644
[21] “Aspartate mutations in presenilin and gamma-secretase inhibitors both impair notch1 proteolysis and nuclear translocation with relative preservation of notch1 signaling.”  Berezovska   10899933
[22] “Separation of presenilin function in amyloid beta-peptide generation and endoproteolysis of Notch.”  Kulic   10811883
[23] “Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex.”  Baki   11226248
[24] “Identification of the presenilins in hematopoietic cells with localization of presenilin 1 to neutrophil and platelet granules.”  Mirinics   11987239
[25] “Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein.”  Sai   11799129
[26] “A new splice variant of glial fibrillary acidic protein GFAPepsilon, interacts with the presenilin proteins.”  Nielsen   12058025
[27] “Presenilin 1 is involved in maturation and trafficking of N-cadherin to the plasma membrane.”  Uemura   14515347
[28] “Reconstitution of gamma-secretase activity.”  Edbauer   12679784
[29] “Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2.”  Kimberly   12740439
[30] “An unappreciated role for RNA surveillance.”  Hillman   14759258
[31] “Phosphorylation of presenilin 1 at the caspase recognition site regulates its proteolytic processing and the progression of apoptosis.”  Fluhrer   14576165
[32] “Conserved residues within the putative active site of gamma-secretase differentially influence enzyme activity and inhibitor binding.”  Wrigley   15341515
[33] “Cadherins mediate both the association between PS1 and beta-catenin and the effects of PS1 on beta-catenin stability.”  Serban   16126725
[34] “Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.”  Olsen   17081983
[35] “C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation.”  Wang   16305624
[36] “The presenilin genes: a new gene family involved in Alzheimer disease pathology.”  Cruts   8875251
[37] “Presenilin mutations in Alzheimer's disease.”  Cruts   9521418
[38] “Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.”  Daub   18691976
[39] “Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.”  Mayya   19690332
[40] “Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3.”  Cruts   8634711
[41] “Mutations of the presenilin I gene in families with early-onset Alzheimer's disease.”  Campion   8634712
[42] “Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.”  Rogaev   7651536
[43] “The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families.”  Clark   7550356
[44] “Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families.”  Kamino   8733303
[45] “Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation.”  Crook   9225696
[46] “E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles.”  Lendon   9298817
[47] “Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype.”  Kwok   9172170
[48] “A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with early onset Alzheimer disease.”  Ramirez-Duenas   9833068
[49] “The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer's disease.”  Mattila   9851443
[50] “Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism.”  Aldudo   9851450
[51] “Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease.”  Cruts   9384602
[52] “Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene.”  Poorkaj   9521423
[53] “Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in a French family with early-onset Alzheimer's disease and transmission study by mismatch enhanced allele specific amplification.”  Besancon   10200054
[54] “De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases.”  Dumanchin   9719376
[55] “A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years.”  Wisniewski   9507958
[56] “Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease.”  Taddei   9831473
[57] “The Glu318Gly substitution in presenilin 1 is not causally related to Alzheimer disease.”  Dermaut   9915968
[58] “Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum.”  Campion   10441572
[59] “Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset Alzheimer's disease in the UK.”  Palmer   10090481
[60] “A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer's disease.”  Sugiyama   10447269
[61] “DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin-1 gene: two novel mutations.”  Aldudo   10533070
[62] “A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and myoclonic seizures.”  Ezquerra   10025789
[63] “Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene.”  Smith   10208579
[64] “A presenilin-1 Thr116Asn substitution in a family with early-onset Alzheimer's disease.”  Romero   10439444
[65] “High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes.”  Finckh   10631141
[66] “Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy.”  Yasuda   10644793
[67] “The presenilin 1 C92S mutation increases abeta 42 production.”  Lewis   11027672
[68] “Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation.”  Raux   11094121
[69] “A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families.”  Athan   11710891
[70] “Molecular evidence of presenilin 1 mutation in familial early onset dementia.”  Matsubara-Tsutsui   11920851
[71] “Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production.”  Moehlmann   12048239
[72] “A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease.”  Bertoli-Avella   12484344
[73] “Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy.”  Kwok   12493737
[74] “Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin syndrome.”  Cornier   18485326
2KR6   5A63   4UIS   5FN2   5FN3   5FN4   5FN5     

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