FE65 AND THE PROTEIN NETWORK CENTERED AROUND THE CYTOSOLIC DOMAIN OF THE ALZHEIMERS BETA-AMYLOID PRECURSOR PROTEIN

A distinctive tract of all the forms of Alzheimer's disease is the ext racellular deposition of a 40-42/43 amino acid-long peptide derived fr om the so-called beta-amyloid precursor protein (APP), This is a membr ane protein of unknown function, whose short cytosolic domain has been recently demonstrated to interact with several proteins. One of these proteins, named Fe65, has the characteristics of an adaptor protein; in fact, it possesses three protein-protein interaction domains: a WW domain and two PID/PTB domains. The interaction with APP requires the most C-terminal PID/PTB domain, whereas the WW domain is responsible f or the interaction with various proteins, one of which was demonstrate d to be the mammalian homolog of the Drosophila enabled protein (Mena) , which in turn interacts with the cytoskeleton, The second PID/PTB do main of Fe65 binds to the CP2/LSF/LBP1 protein, which is an already kn own transcription factor. The other proteins interacting with the cyto solic domain of APP are the G(o) heterotrimeric protein, APP-BP1 and X 11, The latter interacts with APP through a PID/PTB domain and possess es two other protein-protein interaction domains. The small size of th e APP cytodomain and the overlapping of its regions involved in the bi nding of Fe65 and X11 suggest the existence of competitive mechanisms regulating the binding of the various ligands to this cytosolic domain . In this short review the possible functional roles of this complex p rotein network and its involvement in the generation of Alzheimer's ph enotype are discussed. (C) 1998 Federation of European Biochemical Soc ieties.