Functional and topological analysis of PSENEN, the fourth subunit of the γ-secretase complex.
J Biol Chem
; 300(1): 105533, 2024 Jan.
Article
in En
| MEDLINE
| ID: mdl-38072061
ABSTRACT
The γ-secretase complexes are intramembrane cleaving proteases involved in the generation of the Aß peptides in Alzheimer's disease. The complex consists of four subunits, with Presenilin harboring the catalytic site. Here, we study the role of the smallest subunit, PSENEN or Presenilin enhancer 2, encoded by the gene Psenen, in vivo and in vitro. We find a profound Notch deficiency phenotype in Psenen-/- embryos confirming the essential role of PSENEN in the γ-secretase complex. We used Psenen-/- fibroblasts to explore the structure-function of PSENEN by the scanning cysteine accessibility method. Glycine 22 and proline 27, which border the membrane domains 1 and 2 of PSENEN, are involved in complex formation and stabilization of γ-secretase. The hairpin structured hydrophobic membrane domains 1 and 2 are exposed to a water-containing cavity in the complex, while transmembrane domain 3 is not water exposed. We finally demonstrate the essential role of PSENEN for the cleavage activity of the complex. PSENEN is more than a structural component of the γ-secretase complex and might contribute to the catalytic mechanism of the enzyme.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Amyloid Precursor Protein Secretases
Limits:
Animals
Language:
En
Journal:
J Biol Chem
Year:
2024
Type:
Article
Affiliation country:
Belgium