RGD Reference Report - Aph-1 associates directly with full-length and C-terminal fragments of gamma-secretase substrates. - Rat Genome Database

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Aph-1 associates directly with full-length and C-terminal fragments of gamma-secretase substrates.

Authors: Chen, AC  Guo, LY  Ostaszewski, BL  Selkoe, DJ  LaVoie, MJ 
Citation: Chen AC, etal., J Biol Chem. 2010 Apr 9;285(15):11378-91. doi: 10.1074/jbc.M109.088815. Epub 2010 Feb 9.
RGD ID: 7242200
Pubmed: PMID:20145246   (View Abstract at PubMed)
PMCID: PMC2857016   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M109.088815   (Journal Full-text)

Gamma-secretase is a ubiquitous, multiprotein enzyme composed of presenilin, nicastrin, Aph-1, and Pen-2. It mediates the intramembrane proteolysis of many type 1 proteins, plays an essential role in numerous signaling pathways, and helps drive the pathogenesis of Alzheimer disease by excising the hydrophobic, aggregation-prone amyloid beta-peptide from the beta-amyloid precursor protein. A central unresolved question is how its many substrates bind and enter the gamma-secretase complex. Here, we provide evidence that both the beta-amyloid precursor protein holoprotein and its C-terminal fragments, the immediate substrates of gamma-secretase, can associate with Aph-1 at overexpressed as well as endogenous protein levels. This association was observed using bi-directional co-immunoprecipitation in multiple systems and detergent conditions, and an beta-amyloid precursor protein-Aph-1 complex was specifically isolated following in situ cross-linking in living cells. In addition, another endogenous canonical gamma-substrate, Jagged, showed association of both its full-length and C-terminal fragment forms with Aph-1. We were also able to demonstrate that this interaction with substrates was conserved across the multiple isoforms of Aph-1 (beta, alphaS, and alphaL), as they were all able to bind beta-amyloid precursor protein with similar affinity. Finally, two highly conserved intramembrane histidines (His-171 and His-197) within Aph-1, which were recently shown to be important for gamma-secretase activity, are required for efficient binding of substrates. Taken together, our data suggest a dominant role for Aph-1 in interacting with gamma-secretase substrates prior to their processing by the proteolytic complex.



Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Aph1aRatprotein binding  IPIJag1 (Rattus norvegicus) RGD 
Jag1Ratprotein binding  IPIAph1a (Rattus norvegicus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Aph1a  (aph-1 homolog A, gamma secretase subunit)
Jag1  (jagged canonical Notch ligand 1)


Additional Information