I recommend this paper. It is very nice work, clever use of molecular biology and mass spec, and very well-written paper. The work is for me the first that really convincingly demonstrates that presenilin gets cleaved by autocatalysis.

View all comments by Bart De Strooper

This is a solid study that provides important confirmation that presenilin is a zymogen that cuts itself (i.e., it is its own “presenilinase”) and that autoproteolysis occurs stepwise, every ~3 amino acids, similar to what is seen with γ-secretase substrates (albeit in the opposite direction, from N- to C-terminus, which is mechanistically puzzling). The finding that FAD mutations in PS1 can change the proportion of the various N-terminal variants of the PS1 C-terminal fragment subunit is a key piece of evidence, as is the observation that aspartate-scanning around the PS1 cleavage site can result in substantial increases in the putative proteolytic intermediates.

The interpretation of the experiments resulted in a model for presenilin activation (Figure 7), in which the hydrophobic portion of the large loop (where the PS1 endoproteolytic cleavage site resides) is bound near the active site, with cleavage, deletion, or mutation of this region, resulting in active γ-secretase that allows substrate lateral entry. The idea of autoproteolysis had been originally put forward in...  Read more

This is a solid study that provides important confirmation that presenilin is a zymogen that cuts itself (i.e., it is its own “presenilinase”) and that autoproteolysis occurs stepwise, every ~3 amino acids, similar to what is seen with γ-secretase substrates (albeit in the opposite direction, from N- to C-terminus, which is mechanistically puzzling). The finding that FAD mutations in PS1 can change the proportion of the various N-terminal variants of the PS1 C-terminal fragment subunit is a key piece of evidence, as is the observation that aspartate-scanning around the PS1 cleavage site can result in substantial increases in the putative proteolytic intermediates.

The interpretation of the experiments resulted in a model for presenilin activation (Figure 7), in which the hydrophobic portion of the large loop (where the PS1 endoproteolytic cleavage site resides) is bound near the active site, with cleavage, deletion, or mutation of this region, resulting in active γ-secretase that allows substrate lateral entry. The idea of autoproteolysis had been originally put forward in Wolfe et al., 1999, in which it was demonstrated that the two conserved transmembrane aspartates in PS1 were absolutely required for PS1 endoproteolysis. In a follow-up Perspective article in Biochemistry several months later, we put forward the notion that cleavage (or deletion in the case of the ΔE9 PS1 FAD mutant) of the hydrophobic portion of the loop results in active γ-secretase that allows substrate lateral entry (see Wolfe et al., 1999; see especially Figure 2). It is gratifying to see that the new results by Fukumori and colleagues confirm these ideas.

References:
Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberley WT, Selkoe DJ. Two Transmembrane Aspartates in Presenilin 1 Required for Presenilin Endoproteolysis and gamma-Secretase Activity. Nature 1999; 398:513-7. Abstract

Wolfe MS, De Los Angeles J, Miller DD, Xia W, Selkoe DJ. Are Presenilins Intramembrane-Cleaving Aspartyl Proteases? Implications for the Molecular Mechanism of Alzheimer’s Disease. Biochemistry 1999; 38:11223-30. Abstract

View all comments by Michael Wolfe