Is the Snark a Boojum?

Abstract

γ-Secretases are responsible for the proteolytic transmembrane cleavage of the Notch receptor and the amyloid β precursor protein (βPP). Presenilin (PS) proteins are known mediators of γ-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 γ-secretase. Herreman et al . demonstrated that embryonic stem cells deficient in PS1 and PS2 were unable to cleave βPP 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 γ-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 γ-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 γ-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 γ-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 γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1. Nat. Cell Biol. 2 : 463-465. [Online Journal]