Sandbox Reserved 1621: Difference between revisions

Gamma secretase (GS) is a transmembrane [https://en.wikipedia.org/wiki/Aspartic_protease aspartatic protease] that catalyzes peptide bond hydrolysis of type I [https://en.wikipedia.org/wiki/Integral_membrane_protein integral membrane proteins] such as [https://en.wikipedia.org/wiki/Notch_signaling_pathway Notch], [https://en.wikipedia.org/wiki/Amyloid_precursor_protein amyloid precursor protein (APP)], and various other substrates. GS recognizes and catalyzes the cleavage of its substrate into 3 residue segments.<ref name="Bolduc" /> Initial APP processing by [https://en.wikipedia.org/wiki/Beta-secretase_1 Beta secretase] includes the 48-residue peptide Aβ48 or the 49-residue peptide Aβ49. GS then cleaves these peptides into a variety of peptide fragments separated by 3 residues; Aβ48 is cleaved into Aβ45, Aβ42, and Aβ38; Aβ49 is cleaved into Aβ46, Aβ43, and Aβ40. [https://en.wikipedia.org/wiki/Amyloid_beta Aβ products] are connected to neurological diseases such as [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease (AD)], with varying length peptide products showing different disease symptoms. The connection between GS and AD has made GS a popular drug target. Although various inhibitors of GS have been identified, no inhibitors have been clinically approved for treating AD, as GS is also linked to important neurological functions and inhibition of these GS functions leads to dangerous side effects upon inhibition.<ref name="Zhou">PMID:30630874</ref> Recent cryo-electron microscopy (cryo-EM) structures of gamma secretase have showcased the complex four subunit architecture of gamma secretase, the dynamics required for substrate recognition and cleavage, and the differential binding of gamma secretase to the substrates APP and Notch.<ref name="Bai_2015"/>,<ref name="Bai"/>,<ref name="Yang">PMID:30598546</ref>,<ref name="Zhou"/>