The AβPP and Notch cleavage sites are not identical, however. AβPP is cleaved in the middle of its TMD, whereas notch is processed close to the C-terminal end. So are they really cleaved by the same enzyme? An international collaboration led by Konrad Beyreuther, University of Heidelberg, Germany, has attempted to answer this question by examining how the length of the AβPP transmembrane domain affects the γ-secretase cleavage site. Their work appeared in the 22 January PNAS online.

The researchers expressed mutated AβPP, with lengthened or shortened TMDs, in Cos7 cells and then determined, by mass spectrometry, the site of cleavage. They found that if two amino acids were removed from the N-terminal, or two amino acids added to the C terminal of the TMD, the cleavage site shifted toward the C-terminus. In contrast, adding two residues to the N-terminal end of the TMD shifted cleavage toward the N terminus. The results show that the site of γ-secretase cleavage is substrate-dependent, supporting the hypothesis that Notch and AβPP are cleaved by the same enzyme.-Tom Fagan.

Reference:Lichtenthaler SF, Beher D, Grimm HS, Wang R, Shearman MS, Masters CL, Beyreuther K. The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain. PNAS. Advanced online publication 22 January 2002. Abstract