Sandbox Reserved 817: Difference between revisions

Structurally, the 501 amino acid sequence of BACE1 belongs to the eukaryotic aspartic proteases of the pepsin family and contains a bilobal structure constituted of by an N- and a C-terminal domains. Both N- and C-domains are formed by highly twisted <scene name='56/568015/Beta_sheet/2'> highly twisted β-sheet </scene> structures and each domain contributes with an aspartic acid to the catalytic module of the enzyme. The ligands containing a positive charged moiety might then be favorable to counteract the negative charged active site. BACE1 has two aspartic protease active site motifs, DTGS (<scene name='56/568015/93-96/2'>residues 93-96</scene>) and DSGT (<scene name='56/568015/289-292/2'>residues 289-292</scene>), and mutation of either aspartic acid renders the enzyme inactive. Like other aspartic proteases, BACE1 has an N-terminal signal sequence (residues 1–21) and a pro-peptide domain (residues 22–45) that are removed post-translationally, so the mature enzyme begins at residue Glu46. Importantly, BACE1 has a single transmembrane domain near its C-terminus (residues 455–480) and a palmitoylated cytoplasmic tail. Thus, BACE1 is a type I membrane  protein with a luminal active site, features predicted for β-secretase. The position of the BACE1 active site within the lumen of intracellular compartments provides the correct topological orientation for cleavage of APP at the β-secretase site. As observed with other aspartic proteases, BACE1 has <scene name='56/568015/Six_cysteines/1'>six luminal cysteine residues</scene> that form three intramolecular disulfide bonds ('''yellow''') and several N-linked glycosylation sites.<ref name="first">PMID:18005427</ref> <ref name="three">PMID:23681056</ref>