LOCUS       NP_001071096             265 aa            linear   PRI 07-FEB-2025
DEFINITION  gamma-secretase subunit APH-1A isoform 1 [Homo sapiens].
ACCESSION   NP_001071096
VERSION     NP_001071096.1
DBSOURCE    REFSEQ: accession NM_001077628.3
KEYWORDS    RefSeq; MANE Select.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (residues 1 to 265)
  AUTHORS   Watanabe,H., Yoshida,C., Hidaka,M., Ogawa,T., Tomita,T. and
            Futai,E.
  TITLE     Specific Mutations in Aph1 Cause gamma-Secretase Activation
  JOURNAL   Int J Mol Sci 23 (1), 507 (2022)
   PUBMED   35008932
  REMARK    GeneRIF: Specific Mutations in Aph1 Cause gamma-Secretase
            Activation.
            Publication Status: Online-Only
REFERENCE   2  (residues 1 to 265)
  AUTHORS   Haenig,C., Atias,N., Taylor,A.K., Mazza,A., Schaefer,M.H., Russ,J.,
            Riechers,S.P., Jain,S., Coughlin,M., Fontaine,J.F., Freibaum,B.D.,
            Brusendorf,L., Zenkner,M., Porras,P., Stroedicke,M., Schnoegl,S.,
            Arnsburg,K., Boeddrich,A., Pigazzini,L., Heutink,P., Taylor,J.P.,
            Kirstein,J., Andrade-Navarro,M.A., Sharan,R. and Wanker,E.E.
  TITLE     Interactome Mapping Provides a Network of Neurodegenerative Disease
            Proteins and Uncovers Widespread Protein Aggregation in Affected
            Brains
  JOURNAL   Cell Rep 32 (7), 108050 (2020)
   PUBMED   32814053
REFERENCE   3  (residues 1 to 265)
  AUTHORS   Luck,K., Kim,D.K., Lambourne,L., Spirohn,K., Begg,B.E., Bian,W.,
            Brignall,R., Cafarelli,T., Campos-Laborie,F.J., Charloteaux,B.,
            Choi,D., Cote,A.G., Daley,M., Deimling,S., Desbuleux,A., Dricot,A.,
            Gebbia,M., Hardy,M.F., Kishore,N., Knapp,J.J., Kovacs,I.A.,
            Lemmens,I., Mee,M.W., Mellor,J.C., Pollis,C., Pons,C.,
            Richardson,A.D., Schlabach,S., Teeking,B., Yadav,A., Babor,M.,
            Balcha,D., Basha,O., Bowman-Colin,C., Chin,S.F., Choi,S.G.,
            Colabella,C., Coppin,G., D'Amata,C., De Ridder,D., De Rouck,S.,
            Duran-Frigola,M., Ennajdaoui,H., Goebels,F., Goehring,L., Gopal,A.,
            Haddad,G., Hatchi,E., Helmy,M., Jacob,Y., Kassa,Y., Landini,S.,
            Li,R., van Lieshout,N., MacWilliams,A., Markey,D., Paulson,J.N.,
            Rangarajan,S., Rasla,J., Rayhan,A., Rolland,T., San-Miguel,A.,
            Shen,Y., Sheykhkarimli,D., Sheynkman,G.M., Simonovsky,E., Tasan,M.,
            Tejeda,A., Tropepe,V., Twizere,J.C., Wang,Y., Weatheritt,R.J.,
            Weile,J., Xia,Y., Yang,X., Yeger-Lotem,E., Zhong,Q., Aloy,P.,
            Bader,G.D., De Las Rivas,J., Gaudet,S., Hao,T., Rak,J.,
            Tavernier,J., Hill,D.E., Vidal,M., Roth,F.P. and Calderwood,M.A.
  TITLE     A reference map of the human binary protein interactome
  JOURNAL   Nature 580 (7803), 402-408 (2020)
   PUBMED   32296183
REFERENCE   4  (residues 1 to 265)
  AUTHORS   Wu,S., Song,W., Wong,C.C.L. and Shi,Y.
  TITLE     Bax inhibitor 1 is a gamma-secretase-independent presenilin-binding
            protein
  JOURNAL   Proc Natl Acad Sci U S A 116 (1), 141-147 (2019)
   PUBMED   30559186
REFERENCE   5  (residues 1 to 265)
  AUTHORS   Szaruga,M., Munteanu,B., Lismont,S., Veugelen,S., Horre,K.,
            Mercken,M., Saido,T.C., Ryan,N.S., De Vos,T., Savvides,S.N.,
            Gallardo,R., Schymkowitz,J., Rousseau,F., Fox,N.C., Hopf,C., De
            Strooper,B. and Chavez-Gutierrez,L.
  TITLE     Alzheimer's-Causing Mutations Shift Abeta Length by Destabilizing
            gamma-Secretase-Abetan Interactions
  JOURNAL   Cell 170 (3), 443-456 (2017)
   PUBMED   28753424
  REMARK    GeneRIF: Using purified PSEN1/Aph1A gamma-secretase and the
            APPC99-3XFLAG substrate, authors show that substrate shortening
            progressively destabilizes the consecutive enzyme-substrate
            complexes that characterize the sequential gamma-secretase
            processing of APP; present a unifying model for how PSEN or APP
            mutations enhance amyloidogenic Abeta production, suggests that
            environmental factors may increase Alzheimer's Disease risk.
            Erratum:[Cell. 2021 Apr 15;184(8):2257-2258. doi:
            10.1016/j.cell.2021.03.058.. PMID: 33861967]
REFERENCE   6  (residues 1 to 265)
  AUTHORS   Luo,W.J., Wang,H., Li,H., Kim,B.S., Shah,S., Lee,H.J.,
            Thinakaran,G., Kim,T.W., Yu,G. and Xu,H.
  TITLE     PEN-2 and APH-1 coordinately regulate proteolytic processing of
            presenilin 1
  JOURNAL   J Biol Chem 278 (10), 7850-7854 (2003)
   PUBMED   12522139
REFERENCE   7  (residues 1 to 265)
  AUTHORS   Gu,Y., Chen,F., Sanjo,N., Kawarai,T., Hasegawa,H., Duthie,M.,
            Li,W., Ruan,X., Luthra,A., Mount,H.T., Tandon,A., Fraser,P.E. and
            St George-Hyslop,P.
  TITLE     APH-1 interacts with mature and immature forms of presenilins and
            nicastrin and may play a role in maturation of presenilin.nicastrin
            complexes
  JOURNAL   J Biol Chem 278 (9), 7374-7380 (2003)
   PUBMED   12471034
  REMARK    GeneRIF: APH-1 binds to presenilins and nicastrin and may play a
            role in maturation of presenilin-nicastrin complexes
REFERENCE   8  (residues 1 to 265)
  AUTHORS   Lee,S.F., Shah,S., Li,H., Yu,C., Han,W. and Yu,G.
  TITLE     Mammalian APH-1 interacts with presenilin and nicastrin and is
            required for intramembrane proteolysis of amyloid-beta precursor
            protein and Notch
  JOURNAL   J Biol Chem 277 (47), 45013-45019 (2002)
   PUBMED   12297508
  REMARK    GeneRIF: These data indicate that mammalian APH-1 (mAPH-1) along
            with presenilin 1 and nicastrin is probably a functional component
            of the gamma-secretase complex required for the intramembrane
            proteolysis of APP and Notch
REFERENCE   9  (residues 1 to 265)
  AUTHORS   Francis,R., McGrath,G., Zhang,J., Ruddy,D.A., Sym,M., Apfeld,J.,
            Nicoll,M., Maxwell,M., Hai,B., Ellis,M.C., Parks,A.L., Xu,W.,
            Li,J., Gurney,M., Myers,R.L., Himes,C.S., Hiebsch,R., Ruble,C.,
            Nye,J.S. and Curtis,D.
  TITLE     aph-1 and pen-2 are required for Notch pathway signaling,
            gamma-secretase cleavage of betaAPP, and presenilin protein
            accumulation
  JOURNAL   Dev Cell 3 (1), 85-97 (2002)
   PUBMED   12110170
REFERENCE   10 (residues 1 to 265)
  AUTHORS   De Strooper,B., Annaert,W., Cupers,P., Saftig,P., Craessaerts,K.,
            Mumm,J.S., Schroeter,E.H., Schrijvers,V., Wolfe,M.S., Ray,W.J.,
            Goate,A. and Kopan,R.
  TITLE     A presenilin-1-dependent gamma-secretase-like protease mediates
            release of Notch intracellular domain
  JOURNAL   Nature 398 (6727), 518-522 (1999)
   PUBMED   10206645
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from DC365601.1, BC020590.1 and
            BI760743.1.
            This sequence is a reference standard in the RefSeqGene project.
            
            Summary: This gene encodes a component of the gamma secretase
            complex that cleaves integral membrane proteins such as Notch
            receptors and beta-amyloid precursor protein. The gamma secretase
            complex contains this gene product, or the paralogous anterior
            pharynx defective 1 homolog B (APH1B), along with the presenilin,
            nicastrin, and presenilin enhancer-2 proteins. The precise function
            of this seven-transmembrane-domain protein is unknown though it is
            suspected of facilitating the association of nicastrin and
            presenilin in the gamma secretase complex as well as interacting
            with substrates of the gamma secretase complex prior to their
            proteolytic processing. Polymorphisms in a promoter region of this
            gene have been associated with an increased risk for developing
            sporadic Alzheimer's disease. Alternative splicing results in
            multiple protein-coding and non-protein-coding transcript variants.
            [provided by RefSeq, Aug 2011].
            
            Transcript Variant: This variant (1) encodes the longest isoform
            (1; also known as isoform L).
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            Transcript exon combination :: BC020590.1, SRR3476690.1095910.1
                                           [ECO:0000332]
            ##Evidence-Data-END##
            
            ##RefSeq-Attributes-START##
            MANE Ensembl match     :: ENST00000369109.8/ ENSP00000358105.3
            RefSeq Select criteria :: based on conservation, expression,
                                      longest protein
            ##RefSeq-Attributes-END##
FEATURES             Location/Qualifiers
     source          1..265
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="1"
                     /map="1q21.2"
     Protein         1..265
                     /product="gamma-secretase subunit APH-1A isoform 1"
                     /note="gamma-secretase subunit APH-1A; aph-1alpha; APH1A
                     gamma secretase subunit; presenilin-stabilization factor;
                     anterior pharynx defective 1 homolog A"
                     /calculated_mol_wt=28865
     Region          3..233
                     /region_name="Aph-1"
                     /note="Aph-1 protein; pfam06105"
                     /db_xref="CDD:461830"
     Site            3..23
                     /site_type="transmembrane region"
                     /note="propagated from UniProtKB/Swiss-Prot (Q96BI3.1)"
     Site            32..52
                     /site_type="transmembrane region"
                     /note="propagated from UniProtKB/Swiss-Prot (Q96BI3.1)"
     Site            69..89
                     /site_type="transmembrane region"
                     /note="propagated from UniProtKB/Swiss-Prot (Q96BI3.1)"
     Site            119..139
                     /site_type="transmembrane region"
                     /note="propagated from UniProtKB/Swiss-Prot (Q96BI3.1)"
     Site            159..179
                     /site_type="transmembrane region"
                     /note="propagated from UniProtKB/Swiss-Prot (Q96BI3.1)"
     Site            187..207
                     /site_type="transmembrane region"
                     /note="propagated from UniProtKB/Swiss-Prot (Q96BI3.1)"
     Site            214..234
                     /site_type="transmembrane region"
                     /note="propagated from UniProtKB/Swiss-Prot (Q96BI3.1)"
     CDS             1..265
                     /gene="APH1A"
                     /gene_synonym="6530402N02Rik; APH-1; APH-1A; CGI-78"
                     /coded_by="NM_001077628.3:207..1004"
                     /note="isoform 1 is encoded by transcript variant 1"
                     /db_xref="CCDS:CCDS41390.1"
                     /db_xref="GeneID:51107"
                     /db_xref="HGNC:HGNC:29509"
                     /db_xref="MIM:607629"
ORIGIN      
        1 mgaavffgct fvafgpafal flitvagdpl rviilvagaf fwlvslllas vvwfilvhvt
       61 drsdarlqyg llifgaavsv llqevfrfay ykllkkadeg laslsedgrs pisirqmayv
      121 sglsfgiisg vfsvinilad algpgvvgih gdspyyflts afltaaiill htfwgvvffd
      181 acerrrywal glvvgshllt sgltflnpwy easllpiyav tvsmglwafi taggslrsiq
      241 rsllcrrqed srvmvysalr ipped
//
