Gamma-secretase is a membrane protein complex with unusual aspartyl protease activity that cleaves a variety of type I transmembrane proteins, such as APP, Notch and E-cadherin, within their transmembranous regions. Gamma-secretase was first recognized because of its role in the production of Abeta peptides that are pathogenic in Alzheimer's disease. There is overwhelming evidence demonstrating that four components, presenilin, nicastrin, APH-1 and PEN-2, are necessary and sufficient for gamma-secretase activity. However, based on the findings of studies conducted on cells overexpressing these four components, the existence of regulatory components of the gamma-secretase complex has been postulated. Recently, an additional subunit of the gamma-secretase complex, membrane protein CD147, has been identified through the purification and characterization of endogenous complexes from HeLa cell membranes. Removal of CD147 from gamma-secretase complexes increases the production of Abeta-peptides. Elucidating the molecular mechanism by which CD147 exerts its effect on the activity of the gamma-secretase complex will help us to further understand the pathogenesis of Alzheimer's disease, and may allow for the development of novel therapeutics.
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