Specific Cleavage of β-Amyloid Precursor Protein by an Integral Membrane Metalloendopeptidase
The β-amyloid precursor protein (ß-APP) is a membrane spanning glycoprotein. The small ß-protein domain within the precursor is presumed to be the source of amyloid found in plaques characteristic of Alzheimer’s Disease. The amino terminus of ß-APP is released from cells by cleavages that produce both potentially amyloidogenic and non-amyloidogenic fragments of the carboxy terminus (Esch et al., 1990; Anderson et al., 1992; Seubert et al., 1993; Golde et al., 1992; Haas et al., 1992; Sisodia, 1992). Attenuating these cleavages could alter the amount of ß-protein produced by cells. To facilitate understanding the cellular processes that control ß-protein production, we have developed a system to identify the proteolytic enzymes involved. The system was used to characterize a cellular activity that cleaves at Lys16 within the ß-protein.
KeywordsElectrophoresis Glutamine Disulfide Thiol Cytosol
Unable to display preview. Download preview PDF.
- Haass, C., M.G. Schlossmacher, A.Y. Hung, C. Vigo-Pelfrey, A. Mellon, B.L. Ostaszewski, I.Google Scholar
- Powers, J.C., and J.W. Harper, 1986, Inhibitors of metalloproteases, Research Monographs in Cell and Tissue Physiology: Protease Inhibitors 12: 219.Google Scholar
- Roberts, S.B., J.A. Ripellino, K.M. Ingalls, N.K. Robakis, and K.M. Felsenstein, 1993, Nonamyloidogenic cleavage of the ß-amyloid precursor protein by an integral membrane metalloendopeptidase, J. Biol. Chem. In Press.Google Scholar
- Sambamurti, K., J. Shioi, J.P. Anderson, M.A. Pappolla, and N.K. Robakis, 1992, Evidence for intracellular cleavage of the Alzheimer’s amyloid precursor in PC12 cells, J. Neurosci. Res. 33: 319329.Google Scholar
- Seubert, P., T. Oltersdorf, M.G. Lee, R. Barbour, C. Blomquist, D.L. Davis, K. Bryant, L.C. Fritz, D. Galasko, L.J. Thal, I. Lieberburg, and D. Schenk, 1993, Secretion of ß-amyloid precursor protein cleaved at the amino terminus of the ß-amyloid peptide, Nature 361, 260–263.PubMedCrossRefGoogle Scholar
- Sisodia, S.S., E.H. Koo, K. Beyreuther, A. Unterbeck, and D.L. Price, 1990, Evidence that fl-amyloid protein in Alzhiemer’s disease is not derived by normal processing, Science 248Google Scholar
- Small, D.H., R.D. Moir, S.J. Fuller, S. Michaelson, A.I. Bush, Q.X. Li, E. Milward, C. Hilbich, A. Weidemann, K. Beyreuther, and C.L. Masters, 1991, A protease activity associated with acetylcholinesterase releases the membrane-bound form of the amyloid protein precursor of Alzheimer’s disease, Biochemistry 30, 10795–10799.PubMedCrossRefGoogle Scholar
- Tagawa, K., T. Kunishita, K. Maruyama, K. Yoshikawa, E. Kominami, T. Tsuchiya, K. Suzuki, T.Google Scholar
- Tabira, H. Sugita, and S. Ishiura, 1991, Alzheimer’s dis,-ase amyloid ß-clipping enzyme (APP secretase): Identification, purification, and characterization of the enzyme, Biochem. Biophys. Res. Commun. 177:377–387.Google Scholar