The many substrates of presenilin/γ-secretase

Abstract

The Alzheimer's disease (AD)-associated amyloid-β protein precursor (AβPP) is cleaved by α-, β-, and presenilin (PS)/γ-secretases through sequential regulated proteolysis. These proteolytic events control the generation of the pathogenic amyloid-β (Aβ) peptide, which excessively accumulates in the brains of individuals afflicted by AD. A growing number of additional proteins cleaved by PS/γ-secretase continue to be discovered. Similarly to AβPP, most of these proteins are type-I transmembrane proteins involved in vital signaling functions regulating cell fate, adhesion, migration, neurite outgrowth, or synaptogenesis. All the identified proteins share common structural features, which are typical for their proteolysis. The consequences of the PS/γ-secretase-mediated cleavage on the function of many of these proteins are largely unknown. Here, we review the current literature on the proteolytic processing mediated by the versatile PS/γ-secretase complex. We begin by discussing the steps of AβPP processing and PS/γ-secretase complex composition and localization, which give clues to how and where the processing of other PS/γ-secretase substrates may take place. Then we summarize the typical features of PS/γ-secretase-mediated protein processing. Finally, we recapitulate the current knowledge on the possible physiological function of PS/γ-secretase-mediated cleavage of specific substrate proteins.

Fig. 1

AβPP processing and Aβ degradation. AβPP is a type-I transmembrane protein undergoing sequential proteolytic processing by α- or β- and γ-secretases. The non-amyloidogenic processing (1a) is initiated by α-secretase (ADAM10 or ADAM17), which cuts AβPP within the Aβ domain and thus excludes Aβ generation. α-secretase cleavage sheds AβPP ectodomain from the membrane, releasing the soluble AβPPα (sAβPPα) and yielding the membrane-bound C83 AβPP C-terminal fragment (CTF). C83 is cleaved by γ-secretase at the ε- and γ-sites, which result in the release of AβPP intracellular domain (AICD) and a p3 peptide, respectively (2a). Alternatively, the ectodomain of AβPP may be cleaved at the N-terminus of the Aβ region by β-secretase (BACE1). This initiates the amyloidogenic processing (1b) of AβPP by releasing the soluble sAβPPβ and producing the membrane-associated C99 AβPP-CTF. C99 is further cleaved by γ-secretase at ε- and γ-sites to release AICD and Aβ (2b). Aβ peptides may be degraded (3) e.g., by Aβ-degrading enzymes IDE (insulin degrading enzyme) or NEP (neprilysin).

Fig. 2

PS/γ-secretase complex. The four components of the functional PS/γ-secretase complex are shown. PS consists of nine transmembrane domains (marked 1–9) and exerts the catalytic activity of the complex. PS topology is somewhat controversial. Here it is presented according to Kornilova et al. [241]. During maturation of the γ-secretase complex, PS undergoes endoproteolysis yielding the N-terminal (NTF) and the C-terminal fragment (CTF). The active aspartate residues in transmembrane domains 6 and 7 are indicated with sparkles. Nicastrin is a type-I transmembrane glycoprotein. Aph-1 consists of seven transmembrane domains (marked 1–7), and its membrane topology is presented according to Fortna et al. [242]. Nicastrin and Aph-1 facilitate the assembly and trafficking of γ-secretase. Pen-2, which promotes PS endoproteolysis, is a hairpin-structured protein with two transmembrane domains. According to Crystal et al. [243], both its N- and C-termini are on the luminal side of the membrane.