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Protein

Gamma-secretase subunit APH-1A

Gene

APH1A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Non-catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12297508, PubMed:12522139, PubMed:12763021, PubMed:12679784, PubMed:25043039, PubMed:26280335). Required for normal gamma-secretase assembly (PubMed:12522139, PubMed:12471034, PubMed:12763021, PubMed:19369254). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable).Curated7 Publications

GO - Molecular functioni

GO - Biological processi

  • amyloid-beta formation Source: UniProtKB
  • amyloid precursor protein catabolic process Source: UniProtKB
  • amyloid precursor protein metabolic process Source: UniProtKB
  • ephrin receptor signaling pathway Source: Reactome
  • membrane protein ectodomain proteolysis Source: HGNC
  • membrane protein intracellular domain proteolysis Source: UniProtKB
  • metanephros development Source: Ensembl
  • Notch receptor processing Source: UniProtKB
  • Notch receptor processing, ligand-dependent Source: Reactome
  • Notch signaling pathway Source: GO_Central
  • positive regulation of apoptotic process Source: Reactome
  • positive regulation of catalytic activity Source: HGNC
  • protein processing Source: HGNC

Keywordsi

Biological processNotch signaling pathway

Enzyme and pathway databases

ReactomeiR-HSA-1251985 Nuclear signaling by ERBB4
R-HSA-193692 Regulated proteolysis of p75NTR
R-HSA-1980150 Signaling by NOTCH4
R-HSA-205043 NRIF signals cell death from the nucleus
R-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606 Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096 NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-3928665 EPH-ephrin mediated repulsion of cells
R-HSA-9013507 NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9017802 Noncanonical activation of NOTCH3
SignaLinkiQ96BI3
SIGNORiQ96BI3

Names & Taxonomyi

Protein namesi
Recommended name:
Gamma-secretase subunit APH-1A
Short name:
APH-1a
Alternative name(s):
Aph-1alpha
Presenilin-stabilization factor
Gene namesi
Name:APH1A
Synonyms:PSF
ORF Names:CGI-78, UNQ579/PRO1141
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000117362.12
HGNCiHGNC:29509 APH1A
MIMi607629 gene
neXtProtiNX_Q96BI3

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 2Lumenal1 Publication1 Publication2
Transmembranei3 – 23Helical; Name=11 PublicationAdd BLAST21
Topological domaini24 – 31Cytoplasmic1 Publication1 Publication8
Transmembranei32 – 52Helical; Name=21 PublicationAdd BLAST21
Topological domaini53 – 68Lumenal1 Publication1 PublicationAdd BLAST16
Transmembranei69 – 89Helical; Name=31 PublicationAdd BLAST21
Topological domaini90 – 118Cytoplasmic1 Publication1 PublicationAdd BLAST29
Transmembranei119 – 139Helical; Name=41 PublicationAdd BLAST21
Topological domaini140 – 158Lumenal1 Publication1 PublicationAdd BLAST19
Transmembranei159 – 179Helical; Name=51 PublicationAdd BLAST21
Topological domaini180 – 186Cytoplasmic1 Publication1 Publication7
Transmembranei187 – 207Helical; Name=61 PublicationAdd BLAST21
Topological domaini208 – 213Lumenal1 Publication1 Publication6
Transmembranei214 – 234Helical; Name=71 PublicationAdd BLAST21
Topological domaini235 – 265Cytoplasmic1 Publication1 PublicationAdd BLAST31

Keywords - Cellular componenti

Endoplasmic reticulum, Golgi apparatus, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi171H → A: Impaired gamma-secretease assembly and reduced proteolytic activity of the gamma-secretase complex. 1 Publication1
Mutagenesisi197H → A: Impaired gamma-secretease assembly and reduced proteolytic activity of the gamma-secretase complex. 1 Publication1

Organism-specific databases

DisGeNETi51107
OpenTargetsiENSG00000117362
PharmGKBiPA142672599

Chemistry databases

ChEMBLiCHEMBL2094135
DrugBankiDB05171 E2012

Polymorphism and mutation databases

BioMutaiAPH1A
DMDMi37077707

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002210501 – 265Gamma-secretase subunit APH-1AAdd BLAST265

Proteomic databases

EPDiQ96BI3
MaxQBiQ96BI3
PaxDbiQ96BI3
PeptideAtlasiQ96BI3
PRIDEiQ96BI3
TopDownProteomicsiQ96BI3-2 [Q96BI3-2]

PTM databases

iPTMnetiQ96BI3
PhosphoSitePlusiQ96BI3
SwissPalmiQ96BI3

Expressioni

Tissue specificityi

Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain. Isoform 1 and isoform 2 are nearly expressed at the same level.1 Publication

Gene expression databases

BgeeiENSG00000117362
CleanExiHS_APH1A
ExpressionAtlasiQ96BI3 baseline and differential
GenevisibleiQ96BI3 HS

Organism-specific databases

HPAiCAB037272

Interactioni

Subunit structurei

The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2 (PubMed:12297508, PubMed:12740439, PubMed:19369254, PubMed:25043039, PubMed:26623517, PubMed:26280335).6 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
NCSTNQ925424EBI-2606935,EBI-998440

Protein-protein interaction databases

BioGridi119296, 22 interactors
CORUMiQ96BI3
DIPiDIP-44671N
IntActiQ96BI3, 18 interactors
MINTiQ96BI3
STRINGi9606.ENSP00000358105

Chemistry databases

BindingDBiQ96BI3

Structurei

Secondary structure

1265
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi3 – 23Combined sources21
Helixi29 – 60Combined sources32
Helixi65 – 102Combined sources38
Turni103 – 106Combined sources4
Beta strandi107 – 109Combined sources3
Helixi114 – 141Combined sources28
Helixi156 – 184Combined sources29
Helixi187 – 205Combined sources19
Turni206 – 208Combined sources3
Helixi210 – 231Combined sources22
Helixi236 – 242Combined sources7

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5A63electron microscopy3.40C1-265[»]
5FN2electron microscopy4.20C1-265[»]
5FN3electron microscopy4.10C1-265[»]
5FN4electron microscopy4.00C1-265[»]
5FN5electron microscopy4.30C1-265[»]
ProteinModelPortaliQ96BI3
SMRiQ96BI3
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the APH-1 family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3972 Eukaryota
ENOG4111FIJ LUCA
GeneTreeiENSGT00390000002049
HOGENOMiHOG000007541
HOVERGENiHBG050541
InParanoidiQ96BI3
KOiK06172
OMAiWSVIFFN
OrthoDBiEOG091G0IH0
PhylomeDBiQ96BI3
TreeFamiTF314362

Family and domain databases

InterProiView protein in InterPro
IPR009294 Aph-1
PANTHERiPTHR12889 PTHR12889, 1 hit
PfamiView protein in Pfam
PF06105 Aph-1, 1 hit

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q96BI3-1) [UniParc]FASTAAdd to basket
Also known as: L, Aph-alpha1

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MGAAVFFGCT FVAFGPAFAL FLITVAGDPL RVIILVAGAF FWLVSLLLAS
60 70 80 90 100
VVWFILVHVT DRSDARLQYG LLIFGAAVSV LLQEVFRFAY YKLLKKADEG
110 120 130 140 150
LASLSEDGRS PISIRQMAYV SGLSFGIISG VFSVINILAD ALGPGVVGIH
160 170 180 190 200
GDSPYYFLTS AFLTAAIILL HTFWGVVFFD ACERRRYWAL GLVVGSHLLT
210 220 230 240 250
SGLTFLNPWY EASLLPIYAV TVSMGLWAFI TAGGSLRSIQ RSLLCRRQED
260
SRVMVYSALR IPPED
Length:265
Mass (Da):28,996
Last modified:December 1, 2001 - v1
Checksum:i8E37984A1DECC263
GO
Isoform 2 (identifier: Q96BI3-2) [UniParc]FASTAAdd to basket
Also known as: S, Aph-alpha2

The sequence of this isoform differs from the canonical sequence as follows:
     246-247: RR → KD
     248-265: Missing.

Show »
Length:247
Mass (Da):26,840
Checksum:i8EECF2236C1EA4A0
GO
Isoform 3 (identifier: Q96BI3-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     39-120: AFFWLVSLLL...PISIRQMAYV → RCSALPTTSCLI

Show »
Length:195
Mass (Da):20,977
Checksum:iA6D104A120AEBFA2
GO

Sequence cautioni

The sequence AAD34072 differs from that shown. Reason: Frameshift at position 243.Curated
The sequence AAN63816 differs from that shown. Reason: Frameshift at position 243.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti236L → I in AAH01230 (PubMed:15489334).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_04542439 – 120AFFWL…QMAYV → RCSALPTTSCLI in isoform 3. 1 PublicationAdd BLAST82
Alternative sequenceiVSP_008355246 – 247RR → KD in isoform 2. 5 Publications2
Alternative sequenceiVSP_008356248 – 265Missing in isoform 2. 5 PublicationsAdd BLAST18

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF508787 mRNA Translation: AAN63816.1 Frameshift.
AY113698 mRNA Translation: AAM61955.1
AY113699 mRNA Translation: AAM61956.1
AF151835 mRNA Translation: AAD34072.1 Frameshift.
AY358951 mRNA Translation: AAQ89310.1
AK027879 mRNA Translation: BAG51389.1
AK075295 mRNA Translation: BAC11529.1
AK298832 mRNA Translation: BAG60962.1
AL138795 Genomic DNA Translation: CAI22811.1
AL138795 Genomic DNA Translation: CAI22812.1
CH471121 Genomic DNA Translation: EAW53565.1
CH471121 Genomic DNA Translation: EAW53566.1
CH471121 Genomic DNA Translation: EAW53567.1
BC001230 mRNA Translation: AAH01230.1
BC008732 mRNA Translation: AAH08732.1
BC009501 mRNA Translation: AAH09501.1
BC015568 mRNA Translation: AAH15568.1
BC017699 mRNA Translation: AAH17699.1
BC020590 mRNA Translation: AAH20590.1
CCDSiCCDS41390.1 [Q96BI3-1]
CCDS41391.1 [Q96BI3-2]
CCDS58025.1 [Q96BI3-3]
RefSeqiNP_001071096.1, NM_001077628.2 [Q96BI3-1]
NP_001230700.1, NM_001243771.1
NP_001230701.1, NM_001243772.1 [Q96BI3-3]
NP_057106.2, NM_016022.3 [Q96BI3-2]
UniGeneiHs.108408
Hs.735911

Genome annotation databases

EnsembliENST00000360244; ENSP00000353380; ENSG00000117362 [Q96BI3-2]
ENST00000369109; ENSP00000358105; ENSG00000117362 [Q96BI3-1]
ENST00000414276; ENSP00000397473; ENSG00000117362 [Q96BI3-3]
GeneIDi51107
KEGGihsa:51107
UCSCiuc001ety.3 human [Q96BI3-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiAPH1A_HUMAN
AccessioniPrimary (citable) accession number: Q96BI3
Secondary accession number(s): B4DQK0
, Q5TB22, Q5TB23, Q969R6, Q9BVG0, Q9Y386
Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 26, 2003
Last sequence update: December 1, 2001
Last modified: February 28, 2018
This is version 149 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health