ID   E5RG63_HUMAN            Unreviewed;       304 AA.
AC   E5RG63;
DT   08-FEB-2011, integrated into UniProtKB/TrEMBL.
DT   08-FEB-2011, sequence version 1.
DT   02-SEP-2026, entry version 100.
DE   RecName: Full=Presenilin {ECO:0000256|RuleBase:RU361148};
DE            EC=3.4.23.- {ECO:0000256|RuleBase:RU361148};
GN   Name=PSEN2 {ECO:0000313|Ensembl:ENSP00000427806.1};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606 {ECO:0000313|Ensembl:ENSP00000427806.1, ECO:0000313|Proteomes:UP000005640};
RN   [1] {ECO:0000313|Ensembl:ENSP00000427806.1, ECO:0000313|Proteomes:UP000005640}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=11237011; DOI=10.1038/35057062;
RG   International Human Genome Sequencing Consortium;
RA   Lander E.S., Linton L.M., Birren B., Nusbaum C., Zody M.C., Baldwin J.,
RA   Devon K., Dewar K., Doyle M., FitzHugh W., Funke R., Gage D., Harris K.,
RA   Heaford A., Howland J., Kann L., Lehoczky J., LeVine R., McEwan P.,
RA   McKernan K., Meldrim J., Mesirov J.P., Miranda C., Morris W., Naylor J.,
RA   Raymond C., Rosetti M., Santos R., Sheridan A., Sougnez C.,
RA   Stange-Thomann N., Stojanovic N., Subramanian A., Wyman D., Rogers J.,
RA   Sulston J., Ainscough R., Beck S., Bentley D., Burton J., Clee C.,
RA   Carter N., Coulson A., Deadman R., Deloukas P., Dunham A., Dunham I.,
RA   Durbin R., French L., Grafham D., Gregory S., Hubbard T., Humphray S.,
RA   Hunt A., Jones M., Lloyd C., McMurray A., Matthews L., Mercer S., Milne S.,
RA   Mullikin J.C., Mungall A., Plumb R., Ross M., Shownkeen R., Sims S.,
RA   Waterston R.H., Wilson R.K., Hillier L.W., McPherson J.D., Marra M.A.,
RA   Mardis E.R., Fulton L.A., Chinwalla A.T., Pepin K.H., Gish W.R.,
RA   Chissoe S.L., Wendl M.C., Delehaunty K.D., Miner T.L., Delehaunty A.,
RA   Kramer J.B., Cook L.L., Fulton R.S., Johnson D.L., Minx P.J., Clifton S.W.,
RA   Hawkins T., Branscomb E., Predki P., Richardson P., Wenning S., Slezak T.,
RA   Doggett N., Cheng J.F., Olsen A., Lucas S., Elkin C., Uberbacher E.,
RA   Frazier M., Gibbs R.A., Muzny D.M., Scherer S.E., Bouck J.B.,
RA   Sodergren E.J., Worley K.C., Rives C.M., Gorrell J.H., Metzker M.L.,
RA   Naylor S.L., Kucherlapati R.S., Nelson D.L., Weinstock G.M., Sakaki Y.,
RA   Fujiyama A., Hattori M., Yada T., Toyoda A., Itoh T., Kawagoe C.,
RA   Watanabe H., Totoki Y., Taylor T., Weissenbach J., Heilig R., Saurin W.,
RA   Artiguenave F., Brottier P., Bruls T., Pelletier E., Robert C., Wincker P.,
RA   Smith D.R., Doucette-Stamm L., Rubenfield M., Weinstock K., Lee H.M.,
RA   Dubois J., Rosenthal A., Platzer M., Nyakatura G., Taudien S., Rump A.,
RA   Yang H., Yu J., Wang J., Huang G., Gu J., Hood L., Rowen L., Madan A.,
RA   Qin S., Davis R.W., Federspiel N.A., Abola A.P., Proctor M.J., Myers R.M.,
RA   Schmutz J., Dickson M., Grimwood J., Cox D.R., Olson M.V., Kaul R.,
RA   Raymond C., Shimizu N., Kawasaki K., Minoshima S., Evans G.A.,
RA   Athanasiou M., Schultz R., Roe B.A., Chen F., Pan H., Ramser J.,
RA   Lehrach H., Reinhardt R., McCombie W.R., de la Bastide M., Dedhia N.,
RA   Blocker H., Hornischer K., Nordsiek G., Agarwala R., Aravind L.,
RA   Bailey J.A., Bateman A., Batzoglou S., Birney E., Bork P., Brown D.G.,
RA   Burge C.B., Cerutti L., Chen H.C., Church D., Clamp M., Copley R.R.,
RA   Doerks T., Eddy S.R., Eichler E.E., Furey T.S., Galagan J., Gilbert J.G.,
RA   Harmon C., Hayashizaki Y., Haussler D., Hermjakob H., Hokamp K., Jang W.,
RA   Johnson L.S., Jones T.A., Kasif S., Kaspryzk A., Kennedy S., Kent W.J.,
RA   Kitts P., Koonin E.V., Korf I., Kulp D., Lancet D., Lowe T.M.,
RA   McLysaght A., Mikkelsen T., Moran J.V., Mulder N., Pollara V.J.,
RA   Ponting C.P., Schuler G., Schultz J., Slater G., Smit A.F., Stupka E.,
RA   Szustakowski J., Thierry-Mieg D., Thierry-Mieg J., Wagner L., Wallis J.,
RA   Wheeler R., Williams A., Wolf Y.I., Wolfe K.H., Yang S.P., Yeh R.F.,
RA   Collins F., Guyer M.S., Peterson J., Felsenfeld A., Wetterstrand K.A.,
RA   Patrinos A., Morgan M.J., de Jong P., Catanese J.J., Osoegawa K.,
RA   Shizuya H., Choi S., Chen Y.J.;
RT   "Initial sequencing and analysis of the human genome.";
RL   Nature 409:860-921(2001).
RN   [2] {ECO:0000313|Ensembl:ENSP00000427806.1, ECO:0000313|Proteomes:UP000005640}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15496913; DOI=10.1038/nature03001;
RG   International Human Genome Sequencing Consortium;
RT   "Finishing the euchromatic sequence of the human genome.";
RL   Nature 431:931-945(2004).
RN   [3] {ECO:0000313|Ensembl:ENSP00000427806.1, ECO:0000313|Proteomes:UP000005640}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16710414; DOI=10.1038/nature04727;
RA   Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA   Scott C.E., Howe K.L., Woodfine K., Spencer C.C., Jones M.C., Gillson C.,
RA   Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA   Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA   Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA   Ashwell R.I., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H.,
RA   Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA   Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C.,
RA   Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R.,
RA   Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A.,
RA   Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.,
RA   Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V.,
RA   Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.,
RA   Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R.,
RA   Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D.,
RA   Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A.,
RA   Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA   Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA   Mashreghi-Mohammadi M., Matthews L., Matthews N.S., McLaren S., Milne S.,
RA   Mistry S., Moore M.J., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A.,
RA   Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S.,
RA   Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G.,
RA   Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S.,
RA   Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A.,
RA   Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L.,
RA   Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z.,
RA   Coulson A., Vaudin M., Sulston J.E., Durbin R., Hubbard T., Wooster R.,
RA   Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA   Beck S., Rogers J., Bentley D.R., Banerjee R., Bryant S.P., Burford D.C.,
RA   Burrill W.D., Clegg S.M., Dhami P., Dovey O., Faulkner L.M., Gribble S.M.,
RA   Langford C.F., Pandian R.D., Porter K.M., Prigmore E.;
RT   "The DNA sequence and biological annotation of human chromosome 1.";
RL   Nature 441:315-321(2006).
RN   [4] {ECO:0000313|Ensembl:ENSP00000427806.1}
RP   IDENTIFICATION.
RG   Ensembl;
RL   Submitted (JAN-2026) to UniProtKB.
CC   -!- FUNCTION: Catalytic subunit of the gamma-secretase complex, an
CC       endoprotease complex that catalyzes the intramembrane cleavage of
CC       integral membrane proteins such as Notch receptors and APP (amyloid-
CC       beta precursor protein). Selectively cleaves late endosomal/lysosomal
CC       localized substrates and generates the prominent pool of intracellular
CC       amyloid beta that contains longer amyloid beta. The holoprotein
CC       functions as a calcium-leak channel that allows the passive movement of
CC       calcium from endoplasmic reticulum to cytosol and is involved in
CC       calcium homeostasis. Is a regulator of mitochondrion-endoplasmic
CC       reticulum membrane tethering and modulates calcium ions shuttling
CC       between ER and mitochondria. {ECO:0000256|ARBA:ARBA00094320}.
CC   -!- FUNCTION: Probable subunit of the gamma-secretase complex, an
CC       endoprotease complex that catalyzes the intramembrane cleavage of
CC       integral membrane proteins such as Notch receptors.
CC       {ECO:0000256|RuleBase:RU361148}.
CC   -!- SUBUNIT: Homodimer; predominantly heterodimer of a N-terminal (NTF) and
CC       a C-terminal (CTF) endoproteolytical fragment. Component of the gamma-
CC       secretase complex, a complex composed of a presenilin homodimer (PSEN1
CC       or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN. Such
CC       minimal complex is sufficient for secretase activity, although other
CC       components may exist. Interacts with DOCK3. Interacts with HERPUD1,
CC       FLNA, FLNB and PARL. Interacts with AP1G1; this interaction is
CC       phosphorylation dependent and directs PSEN2 via early endosome to late
CC       endosome/lysosome. {ECO:0000256|ARBA:ARBA00094601}.
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000256|RuleBase:RU361148}; Multi-pass membrane protein
CC       {ECO:0000256|RuleBase:RU361148}. Golgi apparatus membrane
CC       {ECO:0000256|RuleBase:RU361148}; Multi-pass membrane protein
CC       {ECO:0000256|RuleBase:RU361148}. Endosome membrane
CC       {ECO:0000256|ARBA:ARBA00004608}.
CC   -!- DOMAIN: The PAL motif is required for normal active site conformation.
CC       {ECO:0000256|RuleBase:RU361148}.
CC   -!- SIMILARITY: Belongs to the peptidase A22A family.
CC       {ECO:0000256|ARBA:ARBA00008604, ECO:0000256|RuleBase:RU361148}.
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DR   EMBL; AL359732; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL391628; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   AlphaFoldDB; E5RG63; -.
DR   SMR; E5RG63; -.
DR   MassIVE; E5RG63; -.
DR   ProteomicsDB; 15567; -.
DR   Antibodypedia; 4424; 470 antibodies from 44 providers.
DR   Ensembl; ENST00000472139.2; ENSP00000427806.1; ENSG00000143801.19.
DR   UCSC; uc057pzf.1; human.
DR   HGNC; HGNC:9509; PSEN2.
DR   NIAGADS; ENSG00000143801; -.
DR   VEuPathDB; HostDB:ENSG00000143801; -.
DR   GeneTree; ENSGT00940000157923; -.
DR   HOGENOM; CLU_022975_3_0_1; -.
DR   OMA; WTTITFC; -.
DR   OrthoDB; 20287at2759; -.
DR   ChiTaRS; PSEN2; human.
DR   Proteomes; UP000005640; Chromosome 1.
DR   Bgee; ENSG00000143801; Expressed in body of pancreas and 98 other cell types or tissues.
DR   ExpressionAtlas; E5RG63; baseline and differential.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0000776; C:kinetochore; IEA:UniProtKB-ARBA.
DR   GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-ARBA.
DR   GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IEA:InterPro.
DR   GO; GO:0042987; P:amyloid precursor protein catabolic process; IEA:InterPro.
DR   GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR   GO; GO:0006509; P:membrane protein ectodomain proteolysis; IEA:UniProtKB-ARBA.
DR   GO; GO:0007220; P:Notch receptor processing; IEA:UniProtKB-ARBA.
DR   GO; GO:0016485; P:protein processing; IEA:InterPro.
DR   FunFam; 1.10.472.100:FF:000001; Presenilin; 1.
DR   Gene3D; 1.10.472.100; Presenilin; 1.
DR   InterPro; IPR001493; Pept_A22A_PS2.
DR   InterPro; IPR001108; Peptidase_A22A.
DR   InterPro; IPR006639; Preselin/SPP.
DR   InterPro; IPR042524; Presenilin_C.
DR   PANTHER; PTHR10202; PRESENILIN; 1.
DR   PANTHER; PTHR10202:SF24; PRESENILIN-2; 1.
DR   Pfam; PF01080; Presenilin; 2.
DR   PRINTS; PR01072; PRESENILIN.
DR   PRINTS; PR01074; PRESENILIN2.
DR   SMART; SM00730; PSN; 1.
PE   1: Evidence at protein level;
KW   Endoplasmic reticulum {ECO:0000256|ARBA:ARBA00022824,
KW   ECO:0000256|RuleBase:RU361148}; Endosome {ECO:0000256|ARBA:ARBA00022753};
KW   Golgi apparatus {ECO:0000256|ARBA:ARBA00023034,
KW   ECO:0000256|RuleBase:RU361148};
KW   Hydrolase {ECO:0000256|ARBA:ARBA00022801, ECO:0000256|RuleBase:RU361148};
KW   Membrane {ECO:0000256|ARBA:ARBA00023136, ECO:0000256|RuleBase:RU361148};
KW   Notch signaling pathway {ECO:0000256|ARBA:ARBA00022976,
KW   ECO:0000256|RuleBase:RU361148};
KW   Phosphoprotein {ECO:0000256|ARBA:ARBA00022553};
KW   Protease {ECO:0000256|ARBA:ARBA00022670, ECO:0000256|RuleBase:RU361148};
KW   Proteomics identification {ECO:0007829|PeptideAtlas:E5RG63};
KW   Reference proteome {ECO:0000313|Proteomes:UP000005640};
KW   Transmembrane {ECO:0000256|ARBA:ARBA00022692,
KW   ECO:0000256|RuleBase:RU361148};
KW   Transmembrane helix {ECO:0000256|ARBA:ARBA00022989,
KW   ECO:0000256|RuleBase:RU361148}.
FT   TRANSMEM        27..45
FT                   /note="Helical"
FT                   /evidence="ECO:0000256|RuleBase:RU361148"
FT   TRANSMEM        57..75
FT                   /note="Helical"
FT                   /evidence="ECO:0000256|RuleBase:RU361148"
FT   TRANSMEM        82..100
FT                   /note="Helical"
FT                   /evidence="ECO:0000256|RuleBase:RU361148"
FT   TRANSMEM        106..125
FT                   /note="Helical"
FT                   /evidence="ECO:0000256|RuleBase:RU361148"
FT   TRANSMEM        245..265
FT                   /note="Helical"
FT                   /evidence="ECO:0000256|RuleBase:RU361148"
FT   TRANSMEM        271..290
FT                   /note="Helical"
FT                   /evidence="ECO:0000256|RuleBase:RU361148"
SQ   SEQUENCE   304 AA;  34094 MW;  ACA44C3A83C8C38E CRC64;
     MISVIVVMTI FLVVLYKYRC YKFIHGWLIM SSLMLLFLFT YIYLGEVLKT YNVAMDYPTL
     LLTVWNFGAV GMVCIHWKGP LVLQQAYLIM ISALMALVFI KYLPEWSAWV ILGAISVYDL
     VAVLCPKGPL RMLVETAQER NEPIFPALIY SSAMVWTVGM AKLDPSSQGA LQLPYDPEME
     EDSYDSFGEP SYPEVFEPPL TGYPGEELEE EEERGVKLGL GDFIFYSVLV GKAAATGSGD
     WNTTLACFVA ILIGLCLTLL LLAVFKKALP ALPISITFGL IFYFSTDNLV RPFMDTLASH
     QLYI
//