Biology rarely re-invents the wheel. That is why proponents of the idea that presenilin (PS) and the proteolytic γ-secretases are one and the same will be pleased with a paper in tomorrow's Science by Bruno Martoglio and colleagues at the Swiss Federal Institute of Technology, Zurich, and the Samuel Lunenfeld Institute, Ontario, Canada. These scientists report the discovery of the signal peptide peptidases (SPP), a new family of intramembraneous proteases that have homology to the presenilins, thus lending credence to the notion that presenilins comprise the catalytic core of γ-secretase.
Many researchers in the Alzheimer community have been focusing on γ-secretase, as it is responsible for the proteolytic processing of amyloid precursor protein (AβPP) into the notorious Aβ. It is also thought to similarly cleave the notch receptor, and probably numerous other transmembrane proteins (see related news item, see related news item). However, the protease exists as a large multimeric complex, and this has made the identification of the catalytic component challenging. Although recent affinity purification experiments using γ-secretase inhibitors have isolated presenilin and the glycoprotein nicastrin (see related news item), direct proof of PS involvement in proteolysis, such as reconstituting its activity in a test tube, has remained elusive.
First author Andreas Weihofen et al. used a different type of test tube to prove SPP was a protease-yeast. The authors expressed the putative aspartyl protease in Saccharomyces cerevisiae, which has no known SPP homologs, and found that the genetically engineered cells were capable of proteolytically cleaving the SPP substrate. This suggests that presenilin, by virtue of homology, is also a protease. Furthermore, when the authors mutated one of the essential aspartate residues, proteolytic activity was almost completely abolished. As Michael Wolfe and Dennis Selkoe of Harvard Medical School point out in an accompanying perspective, the only other explanation for these results would be that SPP activated an endogenous protease in the yeast, a possibility they consider highly unlikely-or is it?
Sangram Sisodia, University of Chicago, points out that the authors' own data reveals yeast SPP subfamily members. These subfamily proteins most likely have endogenous partners, and it could be one of these partners that harbors the catalytic site and is activated by the exogenous SPP (see commentary below). This scenario would relegate SPPs and presenilins to the role of helper proteins, a function that has been previously proposed.—Tom Fagan
- Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science. 2002 Jun 21;296(5576):2215-8. PubMed.
- Wolfe MS, Selkoe DJ. Biochemistry. Intramembrane proteases--mixing oil and water. Science. 2002 Jun 21;296(5576):2156-7. PubMed.