APH1A_MOUSE
ID APH1A_MOUSE Reviewed; 265 AA.
AC Q8BVF7; Q8R1T3; Q91VL5;
DT 26-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 26-SEP-2003, sequence version 2.
DT 03-AUG-2022, entry version 163.
DE RecName: Full=Gamma-secretase subunit APH-1A;
DE Short=APH-1a;
DE AltName: Full=Aph-1alpha;
GN Name=Aph1a;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Liver, and Mammary tumor;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 97-265 (ISOFORM 2).
RC STRAIN=C57BL/6J; TISSUE=Cerebellum;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP FUNCTION, SUBUNIT, AND DISRUPTION PHENOTYPE.
RX PubMed=15634781; DOI=10.1523/jneurosci.3814-04.2005;
RA Ma G., Li T., Price D.L., Wong P.C.;
RT "APH-1a is the principal mammalian APH-1 isoform present in gamma-secretase
RT complexes during embryonic development.";
RL J. Neurosci. 25:192-198(2005).
RN [4]
RP FUNCTION, AND SUBUNIT.
RX PubMed=19369254; DOI=10.1074/jbc.m109.000067;
RA Pardossi-Piquard R., Yang S.P., Kanemoto S., Gu Y., Chen F., Boehm C.,
RA Sevalle J., Li T., Wong P.C., Checler F., Schmitt-Ulms G.,
RA St George-Hyslop P., Fraser P.E.;
RT "APH1 polar transmembrane residues regulate the assembly and activity of
RT presenilin complexes.";
RL J. Biol. Chem. 284:16298-16307(2009).
CC -!- FUNCTION: Non-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) (PubMed:15634781, PubMed:19369254). Required
CC for normal gamma-secretase assembly (PubMed:15634781, PubMed:19369254).
CC The gamma-secretase complex plays a role in Notch and Wnt signaling
CC cascades and regulation of downstream processes via its role in
CC processing key regulatory proteins, and by regulating cytosolic CTNNB1
CC levels (Probable). {ECO:0000269|PubMed:15634781,
CC ECO:0000269|PubMed:19369254, 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/PEN2.
CC {ECO:0000269|PubMed:15634781, ECO:0000269|PubMed:19369254}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q96BI3}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q96BI3}. Golgi apparatus, Golgi stack membrane
CC {ECO:0000250|UniProtKB:Q96BI3}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q96BI3}. Note=Predominantly located in the
CC endoplasmic reticulum and in the cis-Golgi.
CC {ECO:0000250|UniProtKB:Q96BI3}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8BVF7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8BVF7-2; Sequence=VSP_008357, VSP_008358;
CC -!- DISRUPTION PHENOTYPE: Full embryonic lethality. No live homozygous
CC embryos are present after 11 dpc. {ECO:0000269|PubMed:15634781}.
CC -!- SIMILARITY: Belongs to the APH-1 family. {ECO:0000305}.
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DR EMBL; BC012406; AAH12406.1; -; mRNA.
DR EMBL; BC024111; AAH24111.1; -; mRNA.
DR EMBL; AK078343; BAC37228.1; -; mRNA.
DR CCDS; CCDS17624.1; -. [Q8BVF7-2]
DR CCDS; CCDS50999.1; -. [Q8BVF7-1]
DR RefSeq; NP_666216.1; NM_146104.3. [Q8BVF7-2]
DR RefSeq; NP_666246.1; NM_146134.2. [Q8BVF7-1]
DR AlphaFoldDB; Q8BVF7; -.
DR SMR; Q8BVF7; -.
DR BioGRID; 230528; 14.
DR ComplexPortal; CPX-4234; Gamma-secretase complex, Aph1a-Psen1 variant.
DR ComplexPortal; CPX-4236; Gamma-secretase complex, Aph1a-Psen2 variant.
DR CORUM; Q8BVF7; -.
DR IntAct; Q8BVF7; 1.
DR MINT; Q8BVF7; -.
DR STRING; 10090.ENSMUSP00000058846; -.
DR TCDB; 4.G.1.1.1; the Gama-secretase (Gama-secretase) family.
DR iPTMnet; Q8BVF7; -.
DR PhosphoSitePlus; Q8BVF7; -.
DR SwissPalm; Q8BVF7; -.
DR EPD; Q8BVF7; -.
DR PaxDb; Q8BVF7; -.
DR PRIDE; Q8BVF7; -.
DR ProteomicsDB; 282134; -. [Q8BVF7-1]
DR ProteomicsDB; 282135; -. [Q8BVF7-2]
DR Antibodypedia; 34020; 364 antibodies from 37 providers.
DR DNASU; 226548; -.
DR Ensembl; ENSMUST00000015894; ENSMUSP00000015894; ENSMUSG00000015750. [Q8BVF7-2]
DR Ensembl; ENSMUST00000056710; ENSMUSP00000058846; ENSMUSG00000015750. [Q8BVF7-1]
DR GeneID; 226548; -.
DR KEGG; mmu:226548; -.
DR UCSC; uc008qlq.2; mouse. [Q8BVF7-1]
DR CTD; 51107; -.
DR MGI; MGI:2385110; Aph1a.
DR VEuPathDB; HostDB:ENSMUSG00000015750; -.
DR eggNOG; KOG3972; Eukaryota.
DR GeneTree; ENSGT00390000002049; -.
DR HOGENOM; CLU_086389_0_0_1; -.
DR InParanoid; Q8BVF7; -.
DR OMA; FFNAFDT; -.
DR PhylomeDB; Q8BVF7; -.
DR TreeFam; TF314362; -.
DR Reactome; R-MMU-1251985; Nuclear signaling by ERBB4.
DR Reactome; R-MMU-193692; Regulated proteolysis of p75NTR.
DR Reactome; R-MMU-205043; NRIF signals cell death from the nucleus.
DR Reactome; R-MMU-3928665; EPH-ephrin mediated repulsion of cells.
DR Reactome; R-MMU-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus.
DR Reactome; R-MMU-9017802; Noncanonical activation of NOTCH3.
DR BioGRID-ORCS; 226548; 2 hits in 70 CRISPR screens.
DR PRO; PR:Q8BVF7; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; Q8BVF7; protein.
DR Bgee; ENSMUSG00000015750; Expressed in ciliary body and 266 other tissues.
DR ExpressionAtlas; Q8BVF7; baseline and differential.
DR Genevisible; Q8BVF7; MM.
DR GO; GO:0005769; C:early endosome; ISO:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IC:ComplexPortal.
DR GO; GO:0070765; C:gamma-secretase complex; ISO:MGI.
DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
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; ISA:MGI.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0099056; C:integral component of presynaptic membrane; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0097060; C:synaptic membrane; ISO:MGI.
DR GO; GO:0008021; C:synaptic vesicle; ISO:MGI.
DR GO; GO:0061133; F:endopeptidase activator activity; IMP:ARUK-UCL.
DR GO; GO:0019899; F:enzyme binding; IPI:ARUK-UCL.
DR GO; GO:0008233; F:peptidase activity; ISA:MGI.
DR GO; GO:0030674; F:protein-macromolecule adaptor activity; ISO:MGI.
DR GO; GO:0042987; P:amyloid precursor protein catabolic process; ISO:MGI.
DR GO; GO:0042982; P:amyloid precursor protein metabolic process; ISO:MGI.
DR GO; GO:0034205; P:amyloid-beta formation; ISO:MGI.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; ISS:UniProtKB.
DR GO; GO:0031293; P:membrane protein intracellular domain proteolysis; ISO:MGI.
DR GO; GO:0001656; P:metanephros development; IMP:MGI.
DR GO; GO:0007220; P:Notch receptor processing; IMP:MGI.
DR GO; GO:0007219; P:Notch signaling pathway; IBA:GO_Central.
DR GO; GO:0043085; P:positive regulation of catalytic activity; ISS:UniProtKB.
DR GO; GO:0010950; P:positive regulation of endopeptidase activity; IMP:ARUK-UCL.
DR GO; GO:0016485; P:protein processing; ISS:UniProtKB.
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; Endoplasmic reticulum; Golgi apparatus; Membrane;
KW Notch signaling pathway; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..265
FT /note="Gamma-secretase subunit APH-1A"
FT /id="PRO_0000221051"
FT TOPO_DOM 1..2
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TRANSMEM 3..23
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TOPO_DOM 24..31
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TRANSMEM 32..52
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TOPO_DOM 53..68
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TRANSMEM 69..89
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TOPO_DOM 90..118
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TRANSMEM 119..139
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TOPO_DOM 140..158
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TRANSMEM 159..179
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TOPO_DOM 180..186
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TRANSMEM 187..207
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TOPO_DOM 208..213
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TRANSMEM 214..234
FT /note="Helical; Name=7"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT TOPO_DOM 235..265
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q96BI3"
FT VAR_SEQ 246..247
FT /note="RR -> KD (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_008357"
FT VAR_SEQ 248..265
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_008358"
SQ SEQUENCE 265 AA; 28986 MW; 1E37922A1DFAA92C CRC64;
MGAAVFFGCT FVAFGPAFSL FLITVAGDPL RVIILVAGAF FWLVSLLLAS VVWFILVHVT
DRSDARLQYG LLIFGAAVSV LLQEVFRFAY YKLLKKADEG LASLSEDGRS PISIRQMAYV
SGLSFGIISG VFSVINILAD ALGPGVVGIH GDSPYYFLTS AFLTAAIILL HTFWGVVFFD
ACERRRYWAL GLVVGSHLLT SGLTFLNPWY EASLLPIYAV TVSMGLWAFI TAGGSLRSIQ
RSLSCRRQED SRVMVYSALR IPPED
