Structural biology of presenilin 1 complexes

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.

The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force

“…Pen-2 is required for maturation of Presenilin; Aph-1a (or Aph-1b) is required for proper assembly of the γ-secretase complex. Finally, Nicastrin, which is not needed for catalytic activity or substrate recognition (Zhao et al, 2010) is involved in complex stabilization and perhaps substrate selection (Li et al, 2014a). The CryoEM data showed that the 20 TM helices adopt a horseshoe-like structure with a Presenilin and a Aph-1 molecule located in the center and the extracellular domain of Nicastrin forming a head domain that sits atop the hollow region of the horseshoe (Figure 1).…”

“…Perhaps the best studied of these parameters has been the Su(H)-paired-sites (SPS, or Su(H)-paired-sites) that were originally described in the Enhancer of split (E(spl) complex in Drosophila and have been found in CRMs of genes from insects to mammals (Bailey and Posakony, 1995; Hass et al, 2015; Liu and Posakony, 2012, 2014; Nellesen et al, 1999). SPS sites consist of two CSL sites that are found in a specific orientation (head-to-head) and spacing (~15 to 17 nucleotides apart).…”

CRISPR Transcriptional Activation Analysis Unmasks an Occult γ-Secretase Processivity Defect in Familial Alzheimer’s Disease Skin Fibroblasts

“…We focused our analysis here on a prototypical pathological process, familial AD (FAD) due to mutations in presenilin (PSEN)-1 or -2 genes, as the underlying genetic cause is partly established and molecular assays for PSEN-associated activities are well described (Levy-Lahad et al, 1995b; Levy-Lahad et al, 1995a; Rogaev et al, 1995; Sherrington et al, 1995; Li et al, 2014; De Strooper and Chavez Gutierrez, 2015). PSENs are essential components of the γ-secretase (GS) complex, which is a heteromultimeric complex required for intramembranous cleavage of substrates such as the βCTF/C99 fragment of amyloid precursor protein (APP) (De Strooper et al, 2012; Andrew et al, 2016; Selkoe and Hardy, 2016).…”

Alzheimer's Disease and Molecular Chaperones: Current Knowledge and the Future of Chaperonotherapy

“…As a typical proteinopathy, AD is characterized by abnormal proteins with mutations or post-translational modifications that interfere with their normal functions and status (soluble or not) and metabolism inside the cell [15][16][17]. Mutant proteins are the amyloid precursor protein (APP) and presinilins 1 and 2 (PS1 and PS2).…”