PathwayStep2820 PathwayStep2823 PathwayStep2821 PathwayStep2822 A third proteolytic cleavage releases NICD Authored: Jassal, B, 2005-01-07 13:14:17 GENE ONTOLOGYGO:0007220 Pubmed10206645 Pubmed12209127 Pubmed15194119 Pubmed15274632 Pubmed9620803 Reactome Database ID Release 43157212 Reactome, http://www.reactome.org ReactomeREACT_691 The third proteolytic cleavage releases the Notch IntraCellular Domain (NICD) from the NEXT fragment. The catalyst for this cleavage is a membrane protease complex called gamma-secretase (GS). GS cleaves type I membrane proteins such as the Notch receptor and amyloid beta-protein precursor (APP, implicated in Alzheimer's disease). GS is made up of 4 components: Presenilin, nicastrin, APH-1 and PEN-2. Presenilins are homodimeric, multipass transmembrane proteins and are believed to be the catalytic core of GS. All aspartyl proteases have two catalytic aspartates and presenilin contains these residues. The others are essential cofactors for the correct function of GS. NEXT4 is cleaved to produce NICD4 NEXT3 is cleaved to produce NICD3 NEXT2 is cleaved to produce NICD2 NEXT1 is cleaved to produce NICD1