The ins and outs of presenilin 1 membrane topology

Mutations of presenilin 1 (PS1) account for up to 60% of early-onset familial Alzheimer's disease (AD) (1). Because PS1 is a polytopic membrane protein, deciphering its topology is crucial to understanding its important functions. Hydropathy analysis of the PS1 primary amino acid sequence identified 10 hydrophobic regions (HR) [see figure 1A of Dewji et al. (2) in this issue of PNAS]. An eight transmembrane domain (TM) topology, where only 8 of 10 HRs traverse membranes with amino (N) and carboxy (C) tails facing the cytoplasm, has been proposed and is generally accepted by most investigators in this field (Fig. 1 A ) (3, 4). In contrast, Dewji and Singer (5) have suggested an alternative in which PS1 has seven TMs with the N tail facing the extracellular space and the C tail facing the cytoplasm (Fig. 1 B ). This view is now confirmed in studies employing immunofluorescence microscopy with monoclonal antibodies specific either to the N tail or the loop, and polyclonal antipeptide antibodies to the C tail of PS1. The authors offer a provocative suggestion that PS1 may be a member of the superfamily of seven-TM heterotrimeric G protein-coupled receptors (2). Fig. 1. Suggested topologies of PS1. The conserved active site aspartate residues D257 and D385 on HR6 and HR8, respectively, are marked with asterisks. The endoproteolytic sites of PS1 are located in HR7, resulting in N- and C-terminal fragments. According to an eight-TM topology ( A ), the loop consists of residues between HR6 and HR8. PS1 is believed to be a catalytic subunit of γ-secretase (see ref. 6 for review). A slightly altered proteolytic activity of this enzyme, in concert with β-secretase, increases production of a more aggregation-prone peptide, Aβ42, rather than Aβ40 from a type I membrane protein, amyloid precursor protein (APP) (6). This increased level …