Sato T, Tang TC, Reubins G, Fei JZ, Fujimoto T, Kienlen-Campard P, Constantinescu SN, Octave JN, Aimoto S, Smith SO. A helix-to-coil transition at the epsilon-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis. Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1421-6. PubMed.

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Comments

  1. Sato et al. provide nice evidence that APP residues 618-660 can form a dimer...under conditions used for analysis by NMR. Under these conditions, the APP transmembrane domain appears to assume a helical conformation until the ε cleavage site, at which point there appears to be some disruption of the helix. Whether the APP substrate forms a dimer or not, this disruption of the helical conformation near the ε cleavage site is consistent with a body of data, primarily from Yasuo Ihara's laboratory, that ε cleavage occurs first.

    Most of the results in this paper involve spectroscopy, and it is difficult to discern the biological relevance of the findings. The single figure with cellular data (Fig. 5) involves the mutation of three residues near the ε cleavage site, showing that mutation to LLL could prevent proteolysis. One cannot conclude from this experiment, as the authors do, that proteolysis is prevented by extending the transmembrane helix; for example, the LLL insertion extends the hydrophobic transmembrane domain and thus may affect what residues are on the extracellular/lumenal juxtamembrane boundary, which is also known to be important for γ-secretase processing. In addition, the Ihara lab showed essentially the same result by incorporating a stretch of tryptophans in this region (Sato et al., 2005).

    References:

    Sato T, Tanimura Y, Hirotani N, Saido TC, Morishima-Kawashima M, Ihara Y. Blocking the cleavage at midportion between gamma- and epsilon-sites remarkably suppresses the generation of amyloid beta-protein. FEBS Lett. 2005 May 23;579(13):2907-12. PubMed.

    View all comments by Michael Wolfe

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  1. Research Brief: APP Unraveled—Structural Model Extols ε Cleavage