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  • Following an endoproteolytic cleavage of C secretase trims

    2022-01-24

    Following an endoproteolytic cleavage of C99, γ-secretase trims the remaining fragment Aβ49 or Aβ48 in successive, mostly three-residue steps. Aβ49 typically gives rise to Aβ46, Aβ43, and Aβ40; whereas Aβ48 usually yields Aβ45 and Aβ42 [59]. The physical basis for this characteristic cleavage pattern was thought to be caused by preferential recognition of a three-residue segment in the substrate []. Intriguingly, when the sizes of the side chains in the three-residue segment follow the bulky-slim-bulky pattern, proteolytic cleavage appeared to be particularly efficient []. The confirmation of this Moxidectin synthesis requires additional investigations, and the putative three-residue recognition pattern should be conveniently visualized by a high-resolution structure of substrate-bound γ-secretase. Notwithstanding the advances on the cryo-EM structure of γ-secretase, some important questions remain unanswered. For example, how does γ-secretase recognize and deliver the substrate to the active site? How do the AD-associated PS1 mutations affect the cleavage of substrate? How do the inhibitors and modulators target γ-secretase? The substrate-bound and ligand-bound structures are in high demand. Well-controlled in vitro biochemical analyses must be combined with in vivo studies and clinical observations to uncover the functional mechanism of γ-secretase and perhaps the basis for AD development.
    Conflicts of interest
    References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
    Acknowledgements We apologize to those colleagues whose important contributions are not cited in this article due to space limitation. This work was supported by funds from the Ministry of Science and Technology and the National Natural Science Foundation of China.
    Introduction In concert with three other proteins, APH1, PEN2, and Nicastrin, presenilin 1 (PSEN1) or 2 (PSEN2) function as the catalytic core of the intramembrane cleaving protease called γ-secretase [1], [2], [3]. This multi-subunit protease cleaves within the transmembrane domains (TMDs) of over 100 type 1 membrane proteins [4]. γ-Secretase was originally identified as the protease responsible for the generation of Aβ, and thus considered a prime therapeutic target in Alzheimer's disease (AD) [5], [6]. However, it was soon recognized that γ-secretase catalyzed cleavages regulate a variety of signaling events by untethering the cytoplasmic domain of various transmembrane proteins from the membrane, allowing these domains to transduce signals to the nucleus [7], [8]. It is now clear that regulated intramembrane proteolysis carried out by γ-secretase is another means for cells to transmit and regulate signals across a lipid bilayer, though in other cases γ-secretase may also play a role in transmembrane protein turnover [9], [10]. γ-Secretase is an unusual protease. It is highly promiscuous in terms of the transmembrane domain (TMD) sequences it cleaves. Although not absolute, major determinants of cleavage appear to be prior ectodomain shedding and co-localization of γ-secretase with the resulting membrane stub in subcellular compartments [11], [12]. Studies of amyloid β protein precursor (APP) and Notch 1 indicate that γ-secretase initially cleaves the TMD of a protein at a site near the cytoplasmic face of the membrane [8], [13], [14], [15]. In APP this initial cleavage is then followed by 3–5 sequential di, tri, or tetrapeptide cleavages [14]. Thus, γ-secretase cleavage of transmembrane protein results in two potentially biologically active fragments: the cytoplasmic intracellular domain and a small secreted peptide. Fig. 1 illustrates the typical processing of a generic type 1 membrane protein by γ-secretase. For most substrates, the initial γ-secretase cleavage site and the extent of processivity have not been defined.