APH1B_HUMAN
ID APH1B_HUMAN Reviewed; 257 AA.
AC Q8WW43; A8K589; Q564N3; Q6UWQ1; Q9H0S0;
DT 26-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 15-MAR-2005, sequence version 3.
DT 03-AUG-2022, entry version 160.
DE RecName: Full=Gamma-secretase subunit APH-1B;
DE Short=APH-1b;
DE AltName: Full=Aph-1beta;
DE AltName: Full=Presenilin-stabilization factor-like;
GN Name=APH1B; Synonyms=PSFL; ORFNames=UNQ688/PRO1328;
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 [MRNA] (ISOFORM 1).
RA Lee H.-J., Kim T.-W.;
RT "PSF is essential for gamma-secretase activity and stabilization of
RT presenilin and nicastrin.";
RL Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND ALTERNATIVE SPLICING.
RX PubMed=15823552; DOI=10.1016/j.bbrc.2005.03.096;
RA Saito S., Takahashi-Sasaki N., Araki W.;
RT "Identification and characterization of a novel human APH-1b splice variant
RT lacking exon 4.";
RL Biochem. Biophys. Res. Commun. 330:1068-1072(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and analysis of
RT 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [9]
RP FUNCTION, AND INTERACTION WITH PSEN1 AND PSEN2.
RC TISSUE=Glioblastoma;
RX PubMed=12297508; DOI=10.1074/jbc.m208164200;
RA Lee S.-F., Shah S., Li H., Yu C., Han W., Yu G.;
RT "Mammalian APH-1 interacts with presenilin and nicastrin and is required
RT for intramembrane proteolysis of amyloid-beta precursor protein and
RT Notch.";
RL J. Biol. Chem. 277:45013-45019(2002).
RN [10]
RP TISSUE SPECIFICITY.
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).
CC -!- FUNCTION: Probable subunit of the gamma-secretase complex, an
CC endoprotease complex that catalyzes the intramembrane cleavage of
CC integral proteins such as Notch receptors and APP (amyloid-beta
CC precursor protein). It probably represents a stabilizing cofactor for
CC the presenilin homodimer that promotes the formation of a stable
CC complex. Probably present in a minority of gamma-secretase complexes
CC compared to APH1A. {ECO:0000269|PubMed:12297508}.
CC -!- SUBUNIT: Probable component of the gamma-secretase complex, a complex
CC composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN),
CC APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for
CC secretase activity, although other components may exist (By
CC similarity). Interacts with PSEN1 and PSEN2. {ECO:0000250,
CC ECO:0000269|PubMed:12297508}.
CC -!- INTERACTION:
CC Q8WW43; P05067: APP; NbExp=3; IntAct=EBI-2606497, EBI-77613;
CC Q8WW43; P23560-2: BDNF; NbExp=3; IntAct=EBI-2606497, EBI-12275524;
CC Q8WW43; P48230: TM4SF4; NbExp=3; IntAct=EBI-2606497, EBI-8650934;
CC Q8WW43; A5PKU2: TUSC5; NbExp=3; IntAct=EBI-2606497, EBI-11988865;
CC Q8WW43; Q6UX27-3: VSTM1; NbExp=3; IntAct=EBI-2606497, EBI-12190699;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Multi-pass membrane
CC protein {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8WW43-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8WW43-2; Sequence=VSP_042945;
CC -!- TISSUE SPECIFICITY: Weakly or not expressed in leukocytes, lung,
CC placenta, small intestine, liver, kidney, spleen thymus, colon,
CC skeletal muscle, heart and brain. {ECO:0000269|PubMed:12740439}.
CC -!- MISCELLANEOUS: [Isoform 2]: Expressed at low levels in most tissues.
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the APH-1 family. {ECO:0000305}.
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DR EMBL; AF508794; AAN63817.1; -; mRNA.
DR EMBL; AB189172; BAD95573.1; -; mRNA.
DR EMBL; AL136671; CAB66606.1; -; mRNA.
DR EMBL; AY358698; AAQ89061.1; -; mRNA.
DR EMBL; AK291204; BAF83893.1; -; mRNA.
DR EMBL; AC016207; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471082; EAW77645.1; -; Genomic_DNA.
DR EMBL; BC020905; AAH20905.1; -; mRNA.
DR CCDS; CCDS10184.1; -. [Q8WW43-1]
DR CCDS; CCDS45276.1; -. [Q8WW43-2]
DR RefSeq; NP_001139118.1; NM_001145646.1. [Q8WW43-2]
DR RefSeq; NP_112591.2; NM_031301.3. [Q8WW43-1]
DR AlphaFoldDB; Q8WW43; -.
DR SMR; Q8WW43; -.
DR BioGRID; 123659; 9.
DR ComplexPortal; CPX-4232; Gamma-secretase complex, APH1B-PSEN2 variant.
DR ComplexPortal; CPX-4233; Gamma-secretase complex, APH1B-PSEN1 variant.
DR CORUM; Q8WW43; -.
DR IntAct; Q8WW43; 7.
DR MINT; Q8WW43; -.
DR STRING; 9606.ENSP00000261879; -.
DR BindingDB; Q8WW43; -.
DR ChEMBL; CHEMBL2094135; -.
DR TCDB; 1.A.121.1.1; the anterior pharynx-defective water channel (aph-wc) family.
DR iPTMnet; Q8WW43; -.
DR PhosphoSitePlus; Q8WW43; -.
DR BioMuta; APH1B; -.
DR DMDM; 61252592; -.
DR EPD; Q8WW43; -.
DR MassIVE; Q8WW43; -.
DR PaxDb; Q8WW43; -.
DR PeptideAtlas; Q8WW43; -.
DR PRIDE; Q8WW43; -.
DR ProteomicsDB; 74860; -. [Q8WW43-1]
DR ProteomicsDB; 74861; -. [Q8WW43-2]
DR Antibodypedia; 56277; 87 antibodies from 18 providers.
DR DNASU; 83464; -.
DR Ensembl; ENST00000261879.10; ENSP00000261879.5; ENSG00000138613.14. [Q8WW43-1]
DR Ensembl; ENST00000380343.8; ENSP00000369700.4; ENSG00000138613.14. [Q8WW43-2]
DR GeneID; 83464; -.
DR KEGG; hsa:83464; -.
DR MANE-Select; ENST00000261879.10; ENSP00000261879.5; NM_031301.4; NP_112591.2.
DR UCSC; uc002ama.4; human. [Q8WW43-1]
DR CTD; 83464; -.
DR DisGeNET; 83464; -.
DR GeneCards; APH1B; -.
DR HGNC; HGNC:24080; APH1B.
DR HPA; ENSG00000138613; Tissue enriched (testis).
DR MIM; 607630; gene.
DR neXtProt; NX_Q8WW43; -.
DR OpenTargets; ENSG00000138613; -.
DR PharmGKB; PA142672600; -.
DR VEuPathDB; HostDB:ENSG00000138613; -.
DR eggNOG; KOG3972; Eukaryota.
DR GeneTree; ENSGT00390000002049; -.
DR HOGENOM; CLU_086389_0_0_1; -.
DR InParanoid; Q8WW43; -.
DR OMA; EKKKWYV; -.
DR OrthoDB; 1085102at2759; -.
DR PhylomeDB; Q8WW43; -.
DR TreeFam; TF314362; -.
DR PathwayCommons; Q8WW43; -.
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; Q8WW43; -.
DR SIGNOR; Q8WW43; -.
DR BioGRID-ORCS; 83464; 9 hits in 1074 CRISPR screens.
DR ChiTaRS; APH1B; human.
DR GenomeRNAi; 83464; -.
DR Pharos; Q8WW43; Tbio.
DR PRO; PR:Q8WW43; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; Q8WW43; protein.
DR Bgee; ENSG00000138613; Expressed in left testis and 170 other tissues.
DR ExpressionAtlas; Q8WW43; baseline and differential.
DR Genevisible; Q8WW43; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
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:ARUK-UCL.
DR GO; GO:0000139; C:Golgi membrane; IC:ComplexPortal.
DR GO; GO:0016021; C:integral component of membrane; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0030133; C:transport vesicle; IDA:LIFEdb.
DR GO; GO:0061133; F:endopeptidase activator activity; IMP:ARUK-UCL.
DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IMP:ARUK-UCL.
DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ARUK-UCL.
DR GO; GO:0034205; P:amyloid-beta formation; IDA:ARUK-UCL.
DR GO; GO:0007220; P:Notch receptor processing; IDA:ARUK-UCL.
DR GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central.
DR GO; GO:0010950; P:positive regulation of endopeptidase activity; IMP:ARUK-UCL.
DR GO; GO:0016485; P:protein processing; IDA:ARUK-UCL.
DR InterPro; IPR009294; Aph-1.
DR PANTHER; PTHR12889; PTHR12889; 1.
DR Pfam; PF06105; Aph-1; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Membrane; Notch signaling pathway;
KW Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..257
FT /note="Gamma-secretase subunit APH-1B"
FT /id="PRO_0000221052"
FT TRANSMEM 5..25
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TRANSMEM 32..52
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TRANSMEM 71..91
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TRANSMEM 115..135
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TRANSMEM 158..178
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TRANSMEM 186..206
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TRANSMEM 213..233
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT VAR_SEQ 119..159
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15823552"
FT /id="VSP_042945"
FT VARIANT 217
FT /note="F -> L (in dbSNP:rs1047552)"
FT /id="VAR_048315"
FT CONFLICT 27
FT /note="T -> I (in Ref. 4; AAQ89061)"
FT /evidence="ECO:0000305"
FT CONFLICT 83
FT /note="Q -> R (in Ref. 1; AAN63817 and 3; CAB66606)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 257 AA; 28460 MW; A7A0C0076E20990A CRC64;
MTAAVFFGCA FIAFGPALAL YVFTIATEPL RIIFLIAGAF FWLVSLLISS LVWFMARVII
DNKDGPTQKY LLIFGAFVSV YIQEMFRFAY YKLLKKASEG LKSINPGETA PSMRLLAYVS
GLGFGIMSGV FSFVNTLSDS LGPGTVGIHG DSPQFFLYSA FMTLVIILLH VFWGIVFFDG
CEKKKWGILL IVLLTHLLVS AQTFISSYYG INLASAFIIL VLMGTWAFLA AGGSCRSLKL
CLLCQDKNFL LYNQRSR
