PEN2_HUMAN
ID PEN2_HUMAN Reviewed; 101 AA.
AC Q9NZ42; B2R5L9;
DT 26-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 174.
DE RecName: Full=Gamma-secretase subunit PEN-2;
DE AltName: Full=Presenilin enhancer protein 2;
GN Name=PSENEN; Synonyms=PEN2; ORFNames=MDS033;
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;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Hematopoietic stem cell;
RA Zhao M., Gu J., Li N., Peng Y., Han Z., Chen Z.;
RT "Novel genes expressed in hematopoietic stem/progenitor cells from
RT myelodysplastic syndrome patients.";
RL Submitted (DEC-1999) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP INTERACTION WITH NCSTN; PSEN1 AND PSEN2, SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=12198112; DOI=10.1074/jbc.c200469200;
RA Steiner H., Winkler E., Edbauer D., Prokop S., Basset G., Yamasaki A.,
RA Kostka M., Haass C.;
RT "PEN-2 is an integral component of the gamma-secretase complex required for
RT coordinated expression of presenilin and nicastrin.";
RL J. Biol. Chem. 277:39062-39065(2002).
RN [5]
RP TISSUE SPECIFICITY.
RX PubMed=12110170; DOI=10.1016/s1534-5807(02)00189-2;
RA Francis R., McGrath G., Zhang J., Ruddy D.A., Sym M., Apfeld J., Nicoll M.,
RA Maxwell M., Hai B., Ellis M.C., Parks A.L., Xu W., Li J., Gurney M.,
RA Myers R.L., Himes C.S., Hiebsch R., Ruble C., Nye J.S., Curtis D.;
RT "aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase
RT cleavage of betaAPP, and presenilin protein accumulation.";
RL Dev. Cell 3:85-97(2002).
RN [6]
RP SUBCELLULAR LOCATION, FUNCTION, AND SUBUNIT.
RX PubMed=12522139; DOI=10.1074/jbc.c200648200;
RA Luo W.-J., Wang H., Li H., Kim B.S., Shah S., Lee H.-J., Thinakaran G.,
RA Kim T.-W., Yu G., Xu H.;
RT "PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin
RT 1.";
RL J. Biol. Chem. 278:7850-7854(2003).
RN [7]
RP MEMBRANE TOPOLOGY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF GLU-10; ALA-46
RP AND SER-93.
RX PubMed=12639958; DOI=10.1074/jbc.m213107200;
RA Crystal A.S., Morais V.A., Pierson T.C., Pijak D.S., Carlin D., Lee V.M.,
RA Doms R.W.;
RT "Membrane topology of gamma-secretase component PEN-2.";
RL J. Biol. Chem. 278:20117-20123(2003).
RN [8]
RP FUNCTION IN THE GAMMA-SECRETASE COMPLEX.
RX PubMed=12763021; DOI=10.1016/s0006-291x(03)00797-6;
RA Marlow L., Canet R.M., Haugabook S.J., Hardy J.A., Lahiri D.K.,
RA Sambamurti K.;
RT "APH1, PEN2, and nicastrin increase Abeta levels and gamma-secretase
RT activity.";
RL Biochem. Biophys. Res. Commun. 305:502-509(2003).
RN [9]
RP TISSUE SPECIFICITY, FUNCTION, COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH
RP APH1A; PSEN1/PSEN2 AND NCSTN, AND SUBUNIT.
RX PubMed=12740439; DOI=10.1073/pnas.1037392100;
RA Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S.,
RA Selkoe D.J.;
RT "Gamma-secretase is a membrane protein complex comprised of presenilin,
RT nicastrin, Aph-1, and Pen-2.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:6382-6387(2003).
RN [10]
RP ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX.
RX PubMed=12679784; DOI=10.1038/ncb960;
RA Edbauer D., Winkler E., Regula J.T., Pesold B., Steiner H., Haass C.;
RT "Reconstitution of gamma-secretase activity.";
RL Nat. Cell Biol. 5:486-488(2003).
RN [11]
RP INVOLVEMENT IN ACNINV2.
RX PubMed=20929727; DOI=10.1126/science.1196284;
RA Wang B., Yang W., Wen W., Sun J., Su B., Liu B., Ma D., Lv D., Wen Y.,
RA Qu T., Chen M., Sun M., Shen Y., Zhang X.;
RT "Gamma-secretase gene mutations in familial acne inversa.";
RL Science 330:1065-1065(2010).
RN [12]
RP FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-15; PHE-25;
RP LEU-26; TRP-30; ASN-33; TRP-36; LYS-54 AND PHE-94.
RX PubMed=24941111; DOI=10.1021/bi500489j;
RA Holmes O., Paturi S., Selkoe D.J., Wolfe M.S.;
RT "Pen-2 is essential for gamma-secretase complex stability and trafficking
RT but partially dispensable for endoproteolysis.";
RL Biochemistry 53:4393-4406(2014).
RN [13]
RP STRUCTURE BY ELECTRON MICROSCOPY (4.5 ANGSTROMS), FUNCTION, SUBCELLULAR
RP LOCATION, TOPOLOGY, AND SUBUNIT.
RX PubMed=25043039; DOI=10.1038/nature13567;
RA Lu P., Bai X.C., Ma D., Xie T., Yan C., Sun L., Yang G., Zhao Y., Zhou R.,
RA Scheres S.H., Shi Y.;
RT "Three-dimensional structure of human gamma-secretase.";
RL Nature 512:166-170(2014).
RN [14]
RP STRUCTURE BY ELECTRON MICROSCOPY (4.00 ANGSTROMS), SUBUNIT, SUBCELLULAR
RP LOCATION, AND TOPOLOGY.
RX PubMed=26623517; DOI=10.7554/elife.11182;
RA Bai X.C., Rajendra E., Yang G., Shi Y., Scheres S.H.;
RT "Sampling the conformational space of the catalytic subunit of human gamma-
RT secretase.";
RL Elife 4:0-0(2015).
RN [15]
RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), FUNCTION, SUBCELLULAR
RP LOCATION, TOPOLOGY, AND SUBUNIT.
RX PubMed=26280335; DOI=10.1038/nature14892;
RA Bai X.C., Yan C., Yang G., Lu P., Ma D., Sun L., Zhou R., Scheres S.H.,
RA Shi Y.;
RT "An atomic structure of human gamma-secretase.";
RL Nature 525:212-217(2015).
RN [16]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS), SUBUNIT, FUNCTION, AND
RP TOPOLOGY.
RX PubMed=30598546; DOI=10.1038/s41586-018-0813-8;
RA Yang G., Zhou R., Zhou Q., Guo X., Yan C., Ke M., Lei J., Shi Y.;
RT "Structural basis of Notch recognition by human gamma-secretase.";
RL Nature 565:192-197(2019).
RN [17]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS), SUBUNIT, FUNCTION, AND
RP TOPOLOGY.
RX PubMed=30630874; DOI=10.1126/science.aaw0930;
RA Zhou R., Yang G., Guo X., Zhou Q., Lei J., Shi Y.;
RT "Recognition of the amyloid precursor protein by human gamma-secretase.";
RL Science 0:0-0(2019).
CC -!- FUNCTION: Essential 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) (PubMed:12522139, PubMed:12763021,
CC PubMed:12740439, PubMed:12679784, PubMed:24941111, PubMed:30598546,
CC PubMed:30630874). The gamma-secretase complex plays a role in Notch and
CC Wnt signaling cascades and regulation of downstream processes via its
CC role in processing key regulatory proteins, and by regulating cytosolic
CC CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of
CC presenilin and gamma-secretase activity (PubMed:12522139,
CC PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111).
CC {ECO:0000269|PubMed:12522139, ECO:0000269|PubMed:12679784,
CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:12763021,
CC ECO:0000269|PubMed:24941111, ECO:0000269|PubMed:30598546,
CC ECO:0000269|PubMed:30630874, ECO:0000305}.
CC -!- SUBUNIT: The functional gamma-secretase complex is composed of at least
CC four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin
CC (NCSTN), APH1 (APH1A or APH1B) and PSENEN.
CC {ECO:0000269|PubMed:12198112, ECO:0000269|PubMed:12522139,
CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:24941111,
CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335,
CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546,
CC ECO:0000269|PubMed:30630874}.
CC -!- INTERACTION:
CC Q9NZ42; P05067: APP; NbExp=3; IntAct=EBI-998468, EBI-77613;
CC Q9NZ42; Q9BUF7-2: CRB3; NbExp=3; IntAct=EBI-998468, EBI-17233035;
CC Q9NZ42; Q15438: CYTH1; NbExp=3; IntAct=EBI-998468, EBI-997830;
CC Q9NZ42; P02792: FTL; NbExp=4; IntAct=EBI-998468, EBI-713279;
CC Q9NZ42; P06241: FYN; NbExp=3; IntAct=EBI-998468, EBI-515315;
CC Q9NZ42; Q92542: NCSTN; NbExp=4; IntAct=EBI-998468, EBI-998440;
CC Q9NZ42; P49768: PSEN1; NbExp=4; IntAct=EBI-998468, EBI-297277;
CC Q9NZ42; P49768-2: PSEN1; NbExp=3; IntAct=EBI-998468, EBI-11047108;
CC Q9NZ42; Q12908: SLC10A2; NbExp=3; IntAct=EBI-998468, EBI-18114847;
CC Q9NZ42; Q3KNW5: SLC10A6; NbExp=3; IntAct=EBI-998468, EBI-18159983;
CC Q9NZ42; P49755: TMED10; NbExp=3; IntAct=EBI-998468, EBI-998422;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:12522139, ECO:0000269|PubMed:12639958}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:12639958,
CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335,
CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546,
CC ECO:0000269|PubMed:30630874}. Golgi apparatus, Golgi stack membrane
CC {ECO:0000269|PubMed:12522139, ECO:0000269|PubMed:12639958}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:12639958,
CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335,
CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546,
CC ECO:0000269|PubMed:30630874}. Cell membrane
CC {ECO:0000269|PubMed:24941111}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:12639958, ECO:0000269|PubMed:25043039,
CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517}. Membrane
CC {ECO:0000269|PubMed:12198112}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:12639958, ECO:0000269|PubMed:25043039,
CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517,
CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}.
CC Note=Predominantly located in the endoplasmic reticulum and in the cis-
CC Golgi. {ECO:0000269|PubMed:12639958}.
CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed in leukocytes, lung,
CC placenta, small intestine, liver, kidney, spleen thymus, skeletal
CC muscle, heart and brain. {ECO:0000269|PubMed:12110170,
CC ECO:0000269|PubMed:12740439}.
CC -!- DISEASE: Acne inversa, familial, 2, with or without Dowling-Degos
CC disease (ACNINV2) [MIM:613736]: An autosomal dominant form of acne
CC inversa, a chronic relapsing inflammatory disease of the hair follicles
CC characterized by recurrent draining sinuses, painful skin abscesses,
CC and disfiguring scars. Manifestations typically appear after puberty.
CC Some ACNINV2 patients also exhibit reticulate hyperpigmentation
CC consistent with Dowling-Degos disease. {ECO:0000269|PubMed:20929727}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- SIMILARITY: Belongs to the PEN-2 family. {ECO:0000305}.
CC -!- CAUTION: The high-resolution electron microscopy structures indicate
CC that the N-terminus is cytoplasmic, followed by two short helices that
CC dip into the membrane, but do not cross it (PubMed:26280335). In
CC contrast, results based on mutagenesis to create N-glycosylation sites
CC indicate that the N-terminus is lumenal (PubMed:12639958,
CC PubMed:30598546, PubMed:30630874). Both studies indicate that the C-
CC terminus is lumenal (PubMed:12639958, PubMed:26280335).
CC {ECO:0000269|PubMed:12639958, ECO:0000269|PubMed:26280335,
CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}.
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DR EMBL; AF220053; AAF67646.1; -; mRNA.
DR EMBL; AK312233; BAG35166.1; -; mRNA.
DR EMBL; BC009575; AAH09575.1; -; mRNA.
DR CCDS; CCDS12474.1; -.
DR RefSeq; NP_001268461.1; NM_001281532.2.
DR RefSeq; NP_758844.1; NM_172341.3.
DR PDB; 5A63; EM; 3.40 A; D=1-101.
DR PDB; 5FN2; EM; 4.20 A; D=1-101.
DR PDB; 5FN3; EM; 4.10 A; D=1-101.
DR PDB; 5FN4; EM; 4.00 A; D=1-101.
DR PDB; 5FN5; EM; 4.30 A; D=1-101.
DR PDB; 6IDF; EM; 2.70 A; D=1-101.
DR PDB; 6IYC; EM; 2.60 A; D=1-101.
DR PDB; 6LQG; EM; 3.10 A; D=2-101.
DR PDB; 6LR4; EM; 3.00 A; D=2-101.
DR PDB; 7C9I; EM; 3.10 A; D=2-101.
DR PDB; 7D8X; EM; 2.60 A; D=2-101.
DR PDBsum; 5A63; -.
DR PDBsum; 5FN2; -.
DR PDBsum; 5FN3; -.
DR PDBsum; 5FN4; -.
DR PDBsum; 5FN5; -.
DR PDBsum; 6IDF; -.
DR PDBsum; 6IYC; -.
DR PDBsum; 6LQG; -.
DR PDBsum; 6LR4; -.
DR PDBsum; 7C9I; -.
DR PDBsum; 7D8X; -.
DR AlphaFoldDB; Q9NZ42; -.
DR SMR; Q9NZ42; -.
DR BioGRID; 120953; 83.
DR ComplexPortal; CPX-2176; Gamma-secretase complex, APH1A-PSEN1 variant.
DR ComplexPortal; CPX-4231; Gamma-secretase complex, APH1A-PSEN2 variant.
DR ComplexPortal; CPX-4232; Gamma-secretase complex, APH1B-PSEN2 variant.
DR ComplexPortal; CPX-4233; Gamma-secretase complex, APH1B-PSEN1 variant.
DR CORUM; Q9NZ42; -.
DR DIP; DIP-36337N; -.
DR IntAct; Q9NZ42; 15.
DR MINT; Q9NZ42; -.
DR STRING; 9606.ENSP00000468411; -.
DR BindingDB; Q9NZ42; -.
DR ChEMBL; CHEMBL2374; -.
DR DrugBank; DB05171; E-2012.
DR iPTMnet; Q9NZ42; -.
DR PhosphoSitePlus; Q9NZ42; -.
DR SwissPalm; Q9NZ42; -.
DR BioMuta; PSENEN; -.
DR DMDM; 37081820; -.
DR EPD; Q9NZ42; -.
DR jPOST; Q9NZ42; -.
DR MassIVE; Q9NZ42; -.
DR MaxQB; Q9NZ42; -.
DR PaxDb; Q9NZ42; -.
DR PeptideAtlas; Q9NZ42; -.
DR PRIDE; Q9NZ42; -.
DR ProteomicsDB; 83319; -.
DR TopDownProteomics; Q9NZ42; -.
DR Antibodypedia; 4603; 252 antibodies from 36 providers.
DR DNASU; 55851; -.
DR Ensembl; ENST00000222266.2; ENSP00000222266.1; ENSG00000205155.8.
DR Ensembl; ENST00000587708.7; ENSP00000468411.1; ENSG00000205155.8.
DR GeneID; 55851; -.
DR KEGG; hsa:55851; -.
DR MANE-Select; ENST00000587708.7; ENSP00000468411.1; NM_172341.4; NP_758844.1.
DR UCSC; uc002obi.3; human.
DR CTD; 55851; -.
DR DisGeNET; 55851; -.
DR GeneCards; PSENEN; -.
DR HGNC; HGNC:30100; PSENEN.
DR HPA; ENSG00000205155; Low tissue specificity.
DR MalaCards; PSENEN; -.
DR MIM; 607632; gene.
DR MIM; 613736; phenotype.
DR neXtProt; NX_Q9NZ42; -.
DR OpenTargets; ENSG00000205155; -.
DR Orphanet; 79145; Dowling-Degos disease.
DR Orphanet; 387; NON RARE IN EUROPE: Hidradenitis suppurativa.
DR PharmGKB; PA142671122; -.
DR VEuPathDB; HostDB:ENSG00000205155; -.
DR eggNOG; KOG3402; Eukaryota.
DR GeneTree; ENSGT00390000016319; -.
DR HOGENOM; CLU_124142_2_0_1; -.
DR InParanoid; Q9NZ42; -.
DR OMA; WYFRAGF; -.
DR OrthoDB; 1517974at2759; -.
DR PhylomeDB; Q9NZ42; -.
DR PathwayCommons; Q9NZ42; -.
DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4.
DR Reactome; R-HSA-193692; Regulated proteolysis of p75NTR.
DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus.
DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus.
DR Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants.
DR Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants.
DR Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus.
DR Reactome; R-HSA-3928665; EPH-ephrin mediated repulsion of cells.
DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus.
DR Reactome; R-HSA-9013700; NOTCH4 Activation and Transmission of Signal to the Nucleus.
DR Reactome; R-HSA-9017802; Noncanonical activation of NOTCH3.
DR Reactome; R-HSA-977225; Amyloid fiber formation.
DR SignaLink; Q9NZ42; -.
DR SIGNOR; Q9NZ42; -.
DR BioGRID-ORCS; 55851; 34 hits in 1064 CRISPR screens.
DR ChiTaRS; PSENEN; human.
DR GenomeRNAi; 55851; -.
DR Pharos; Q9NZ42; Tchem.
DR PRO; PR:Q9NZ42; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q9NZ42; protein.
DR Bgee; ENSG00000205155; Expressed in right uterine tube and 95 other tissues.
DR ExpressionAtlas; Q9NZ42; baseline and differential.
DR Genevisible; Q9NZ42; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HGNC-UCL.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IC:ComplexPortal.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0070765; C:gamma-secretase complex; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HGNC-UCL.
DR GO; GO:0032580; C:Golgi cisterna membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000139; C:Golgi membrane; IC:ComplexPortal.
DR GO; GO:0016021; C:integral component of membrane; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:HGNC-UCL.
DR GO; GO:0099056; C:integral component of presynaptic membrane; IEA:Ensembl.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:ComplexPortal.
DR GO; GO:0061133; F:endopeptidase activator activity; IMP:ARUK-UCL.
DR GO; GO:0019899; F:enzyme binding; IPI:ARUK-UCL.
DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ComplexPortal.
DR GO; GO:0042982; P:amyloid precursor protein metabolic process; IDA:UniProtKB.
DR GO; GO:0034205; P:amyloid-beta formation; IMP:UniProtKB.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC-UCL.
DR GO; GO:0031293; P:membrane protein intracellular domain proteolysis; IDA:ComplexPortal.
DR GO; GO:0007220; P:Notch receptor processing; IBA:GO_Central.
DR GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0043085; P:positive regulation of catalytic activity; IDA:HGNC-UCL.
DR GO; GO:0010950; P:positive regulation of endopeptidase activity; IMP:UniProtKB.
DR GO; GO:0016485; P:protein processing; IDA:HGNC-UCL.
DR InterPro; IPR019379; Gamma_Secretase_Asp_P_PEN2.
DR PANTHER; PTHR16318; PTHR16318; 1.
DR Pfam; PF10251; PEN-2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Endoplasmic reticulum; Golgi apparatus;
KW Membrane; Notch signaling pathway; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..101
FT /note="Gamma-secretase subunit PEN-2"
FT /id="PRO_0000190900"
FT TOPO_DOM 1..17
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:26280335"
FT INTRAMEM 18..36
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TOPO_DOM 37..57
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TRANSMEM 58..78
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TOPO_DOM 79..101
FT /note="Lumenal"
FT /evidence="ECO:0000269|PubMed:26280335,
FT ECO:0000305|PubMed:12639958"
FT MUTAGEN 10
FT /note="E->S: Induces a N-linked glycosylation on N-8."
FT /evidence="ECO:0000269|PubMed:12639958"
FT MUTAGEN 15
FT /note="C->A: Decreased APP processing by the gamma-
FT secretase complex."
FT /evidence="ECO:0000269|PubMed:24941111"
FT MUTAGEN 15
FT /note="C->S: No effect on APP processing by the gamma-
FT secretase complex."
FT /evidence="ECO:0000269|PubMed:24941111"
FT MUTAGEN 25
FT /note="F->A: Decreased APP processing by the gamma-
FT secretase complex."
FT /evidence="ECO:0000269|PubMed:24941111"
FT MUTAGEN 26
FT /note="L->A: Decreased APP processing by the gamma-
FT secretase complex."
FT /evidence="ECO:0000269|PubMed:24941111"
FT MUTAGEN 30
FT /note="W->A: Decreased expression levels, and decreased
FT stimulation of presenilin endoproteolysis."
FT /evidence="ECO:0000269|PubMed:24941111"
FT MUTAGEN 33
FT /note="N->A: Increased expression at the cell membrane."
FT /evidence="ECO:0000269|PubMed:24941111"
FT MUTAGEN 36
FT /note="W->A: Decreased APP processing by the gamma-
FT secretase complex."
FT /evidence="ECO:0000269|PubMed:24941111"
FT MUTAGEN 46
FT /note="A->N: No effect."
FT /evidence="ECO:0000269|PubMed:12639958"
FT MUTAGEN 54
FT /note="K->A: Decreased APP processing by the gamma-
FT secretase complex."
FT /evidence="ECO:0000269|PubMed:24941111"
FT MUTAGEN 93
FT /note="S->N: Induces a N-linked glycosylation."
FT /evidence="ECO:0000269|PubMed:12639958"
FT MUTAGEN 94
FT /note="F->A: Decreased APP processing by the gamma-
FT secretase complex."
FT /evidence="ECO:0000269|PubMed:24941111"
FT STRAND 4..6
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 8..20
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 21..23
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 27..42
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 50..81
FT /evidence="ECO:0007829|PDB:6IYC"
FT TURN 82..84
FT /evidence="ECO:0007829|PDB:6IYC"
FT STRAND 85..87
FT /evidence="ECO:0007829|PDB:7C9I"
FT HELIX 88..91
FT /evidence="ECO:0007829|PDB:6IYC"
FT STRAND 92..95
FT /evidence="ECO:0007829|PDB:6IYC"
SQ SEQUENCE 101 AA; 12029 MW; FDBA4D299488EA02 CRC64;
MNLERVSNEE KLNLCRKYYL GGFAFLPFLW LVNIFWFFRE AFLVPAYTEQ SQIKGYVWRS
AVGFLFWVIV LTSWITIFQI YRPRWGALGD YLSFTIPLGT P
