Activation and intrinsic gamma-secretase activity of presenilin 1.

Abstract

A complex composed of presenilin (PS), nicastrin, PEN-2, and APH-1 is absolutely required for γ-secretase activity in vivo. Evidence has emerged to suggest a role for PS as the catalytic subunit of γ-secretase, but it has not been established that PS is catalytically active in the absence of associated subunits. We now report that bacterially synthesized, recombinant PS (rPS) reconstituted into liposomes exhibits γ-secretase activity. Moreover, an rPS mutant that lacks a catalytic aspartate residue neither exhibits reconstituted γ-secretase activity nor interacts with a transition-state γ-secretase inhibitor. Importantly, we demonstrate that rPS harboring mutations that cause early onset familial Alzheimer's disease (FAD) lead to elevations in the ratio of Aβ42 to Aβ40 peptides produced from a wild-type APP substrate and that rPS enhances the Aβ42/Aβ40 peptide ratio from FAD-linked mutant APP substrates, findings that are entirely consistent with the results obtained in in vivo settings. Thus, γ-secretase cleavage specificity is an inherent property of the polypeptide. Finally, we demonstrate that PEN2 is sufficient to promote the endoproteolysis of PS1 to generate the active form of γ-secretase. Thus, we conclusively establish that activated PS is catalytically competent and the bimolecular interaction of PS1 and PEN2 can convert the PS1 zymogen to an active protease.

• Authors: Kwangwook Ahn, Christopher C Shelton, Yuan Tian, Xulun Zhang, M Lane Gilchrist, Sangram S Sisodia, Yue-Ming Li
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 50 Pg. 21435-40 (Dec 14 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 21115843 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Membrane Proteins
• PSEN1 protein, human
• PSENEN protein, human
• Peptide Fragments
• Presenilin-1
• Protein Subunits
• Proteolipids
• Recombinant Proteins
• proteoliposomes
• Amyloid Precursor Protein Secretases

Topics

• Alzheimer Disease (enzymology, genetics)
• Amyloid Precursor Protein Secretases (genetics, metabolism)
• Amyloid beta-Peptides (genetics, metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Enzyme Activation
• Humans
• Membrane Proteins (genetics, metabolism)
• Mutation
• Peptide Fragments (genetics, metabolism)
• Presenilin-1 (genetics, metabolism)
• Protein Subunits (genetics, metabolism)
• Proteolipids (chemistry)
• Recombinant Proteins (genetics, metabolism)