PROTEIN PROTEOLYSIS Is the Snark a Boojum?

Abstract:

-Secretases are responsible for the proteolytic transmembrane cleavage of the Notch receptor and the amyloid ß precursor protein (ßPP). Presenilin (PS) proteins are known mediators of -secretase activity; mutated PS proteins have been found in patients with hereditary Alzheimer's disease. Three recent reports examine the connection between the PS proteins and -secretase. Herreman et al. demonstrated that embryonic stem cells deficient in PS1 and PS2 were unable to cleave ßPP and Notch, whereas Zhang et al. were able to delineate that the presence of PS1 rather than PS2 appears to generate greater cleavage of Notch. Esler et al. used transition-state analog peptidomimetic inhibitors of -secretase and demonstrated through photoaffinity labeling experiments that these inhibitors bound directly to PS1 and PS2. Thus, these reports provide strong evidence that the PS proteins themselves contain the -secretase activity.

Esler, W.P., Kimberly, W.T., Ostaszewski, B.L., Diehl, T.S., Moore, C.L., Tsai, J.-Y., Rahmati, T., Xia, W., Selkoe, D.J., and Wolfe, M.S. (2000) Transition-state analogue inhibitors of -secretase bind directly to presenilin-1. Nature Cell Biol. 2: 428-434. [Online Journal]

Herreman, A., Serneels, L., Annaert, W., Collen, D., Schoonjans, L., and De Strooper, B. (2000) Total inactivation of -secretase activity in presenilin-deficient embryonic stem cells. Nature Cell Biol. 2: 461-462. [Online Journal]

Zhang, Z., Nadeau, P., Song, W., Donoviel, D., Yuan, M., Bernstein, A., and Yankner, B.A. (2000) Presenilins are required for -secretase cleavage of ß-APP and transmembrane cleavage of Notch-1. Nat. Cell Biol. 2: 463-465. [Online Journal]