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O2‐03‐02: Stepwise autoproteolysis of presenilin 1 is affected by familial Alzheimer's disease mutations
Author(s) -
Haass Christian,
Fukumori Akio,
Steiner Harald
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.315
Subject(s) - presenilin , cleavage (geology) , mutant , chemistry , mutagenesis , biochemistry , protein subunit , amyloid precursor protein , amyloid (mycology) , peptide , alzheimer's disease , biology , disease , gene , medicine , inorganic chemistry , paleontology , fracture (geology)
Background: Presenilin (PS1 or PS2) is the catalytic component of the gsecretase complex, which mediates the final proteolytic processing step leading to the Alzheimer’s disease (AD) characterizing Amyloid ß-peptide. PS is proteolytically cleaved during complex assembly into its characteristic Nand C-terminal fragments. Both fragments are integral components of physiologically active g-secretase and harbor the two critical aspartyl residues of the active site domain. While the minimal subunit composition of g-secretase has been defined and numerous substrates were identified, the functional role of PS endoproteolysis for g-secretase activity is unknown and it is not established how PS is cleaved, i.e. by autoproteolysis or an independent proteolytic activity. Methods: All methods used were published previously. Results: We addressed these pivotal questions, by investigating if familial AD (FAD)-associated PS1 mutations affect the precision of PS endoproteolysis in a similar manner like such mutations shift the intramembrane cleavage of g-secretase substrates. We demonstrate that all FAD mutations investigated still allow endoproteolysis to occur. However, the precision of PS1 endoproteolysis is affected by PS1 mutations. Comparing the cleavage products generated by a variety of PS1 mutants revealed that specifically cleavages at positions 293 and 296 of PS1 are selectively affected. Systematic mutagenesis around the cleavage site revealed a stepwise three amino acid spaced cleavage mechanism of PS endoproteolysis highly reminiscent to the e-, z-, and g-cleavages described for native g-secretase substrates, such as the ß-amyloid precusor protein. Conclusions: We conclude that PS1 endoproteolysis occurs in a stepwise manner by autoproteolysis.