Abstract
The presenilin genes were first identified as the site of missense mutations causing early onset autosomal dominant familial Alzheimer's disease. Subsequent work has shown that the presenilin proteins are the catalytic subunits of a hetero-tetrameric complex containing APH1, nicastrin and PEN-2. This complex (variously termed presenilin complex or gamma-secretase complex) performs an unusual type of proteolysis in which the transmembrane domains of Type I proteins are cleaved within the hydrophobic compartment of the membrane. This review describes some of the molecular and structural biology of this unusual enzyme complex. The presenilin complex is a bilobed structure. The head domain contains the ectodomain of nicastrin. The base domain contains a central cavity with a lateral cleft that likely provides the route for access of the substrate to the catalytic cavity within the centre of the base domain. There are reciprocal allosteric interactions between various sites in the complex that affect its function. For instance, binding of Compound E, a peptidomimetic inhibitor to the PS1 N-terminus, induces significant conformational changes that reduces substrate binding at the initial substrate docking site, and thus inhibits substrate cleavage. However, there is a reciprocal allosteric interaction between these sites such that prior binding of the substrate to the initial docking site paradoxically increases the binding of the Compound E peptidomimetic inhibitor. Such reciprocal interactions are likely to form the basis of a gating mechanism that underlies access of substrate to the catalytic site. An increasingly detailed understanding of the structural biology of the presenilin complex is an essential step towards rational design of substrate- and/or cleavage site-specific modulators of presenilin complex function.
Highlights
The presenilin genes were first identified as the site of missense mutations causing early onset autosomal dominant familial Alzheimer's disease
Recent work with gamma-secretase modulator (GSM) compounds has highligted the difficulty in generating substrate-specific inhibitors that potently prevent the generation of amyloidogenic APP cleavage products but exhibit minimal activity toward the cleavage of other substrates such as Notch-1
This review examines the function of the presenilin complexes from a structural perspective and emphasizes aspects of their biology that will need to be understood before rational drug design approaches can be applied to achieve either improved substrate specificity and/or to modulate the species of Aβ produced
Summary
During the assembly and maturation of presenilin complexes, the PS1 or PS2 subunits undergo endoproteolytic cleavage into N- and C-terminal fragments [37,43,44]. Considerable advances in cryo-EM technology, in particular the use of new detectors and image processing methods, enabled further refinements of this model by increasing the image resolution to 4.5 Å [60] (EMD-2677, PDB code 4upc) This higher resolution model confirmed the bi-lobed shape of human presenilin complexes as their native state (Figures 2B and 3B). Following binding of Compound E to a non-catalytic site on PS1-NTF, PS1 complexes undergo several allosteric conformational changes that include: 1) rotation of the nicastrin-containing head domain; and 2) compaction of the membrane embedded base domain with closure of the lateral cleft (Figure 3C) [36]. Whether the substrate accesses via a route between TM6 and TM9 as suggested by some crosslinking studies remains unresolved
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