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Mutation Analysis of the Presenilin 1 N-terminal Domain Reveals a Broad Spectrum of Gamma-Secretase Activity Toward Amyloid Precursor Protein and Other Substrates

Mutation Analysis of the Presenilin 1 N-terminal Domain Reveals a Broad Spectrum of Gamma-Secretase Activity Toward Amyloid Precursor Protein and Other Substrates

Ping Gong, Kulandaivelu S Vetrivel, Phuong D Nguyen, Xavier Meckler, Haipeng Cheng, Maria Z Kounnas, Steven L Wagner, Angèle T Parent, Gopal Thinakaran

J Biol Chem. 2010 Dec 3;285(49):38042-52.

PMID: 20921220

Abstract:

The γ-secretase protein complex executes the intramembrane proteolysis of amyloid precursor protein (APP), which releases Alzheimer disease β-amyloid peptide. In addition to APP, γ-secretase also cleaves several other type I membrane protein substrates including Notch1 and N-cadherin. γ-Secretase is made of four integral transmembrane protein subunits: presenilin (PS), nicastrin, APH1, and PEN2. Multiple lines of evidence indicate that a heteromer of PS-derived N- and C-terminal fragments functions as the catalytic subunit of γ-secretase. Only limited information is available on the domains within each subunit involved in the recognition and recruitment of diverse substrates and the transfer of substrates to the catalytic site. Here, we performed mutagenesis of two domains of PS1, namely the first luminal loop domain (LL1) and the second transmembrane domain (TM2), and analyzed PS1 endoproteolysis as well as the catalytic activities of PS1 toward APP, Notch, and N-cadherin. Our results show that distinct residues within LL1 and TM2 domains as well as the length of the LL1 domain are critical for PS1 endoproteolysis, but not for PS1 complex formation with nicastrin, APH1, and PEN2. Furthermore, our experimental PS1 mutants formed γ-secretase complexes with distinct catalytic properties toward the three substrates examined in this study; however, the mutations did not affect PS1 interaction with the substrates. We conclude that the N-terminal LL1 and TM2 domains are critical for PS1 endoproteolysis and the coordination between the putative substrate-docking site and the catalytic core of the γ-secretase.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248117	Presenilin-1 N-Terminal Peptide			Price

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