. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6382-7. PubMed.


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  1. This is an extremely important paper that, along with recent publications from Iwatsubo et al., 2003 and Haass et al., 2003, finally show that the γ-sceretase complex is composed of four transmembrane proteins: presenillin, nicastrin, Aph-1 and Pen-2. It is a clear and convincing study that builds on previous work from the same group and brings together genetic and biochemical evidence for the structure, function and composition of the γ-sceretase complex in a human cell model system. Kimberly et al. show that these four components are required for the maturation and stability of the complex, and the production of amyloid-β. The challenge now remains to elucidate regulatory mechanisms and substrate-specificity of the complex and to biochemically reconstitute the components in an in-vitro system in order to rationally design inhibitory compounds.


    . The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003 Mar 27;422(6930):438-41. PubMed.

    . Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003 May;5(5):486-8. PubMed.

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