Sandbox Reserved 817: Difference between revisions

BACE1 is the result of the expression of the BACE1 gene localised on chromosome 11 (30kb). This gene is composed of 9 exons that are linked together during the mRNA maturation. BACE1 is expressed in the majority of human tissues however, the highest levels of activity are found in the neuronal cell. This β secretase is a transmembrane protein mainly localised within cholesterol-rich lipid raft. It is found in the acidic compartments of the secretory pathway (mostly endosomes and the Trans Golgi Network) with its catalytic site facing the lumen side. This enzyme is regulated both at the translation and transcription steps and its expression is correlated with cell stress signals.<ref =name"un">PMID: 18005427</ref>

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='56/568015/93-96/1'>residues 93-96</scene>) and DSGT (<scene name='56/568015/289-292/1'>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"un">PMID: 18005427</ref> <ref>PMID: 23681056</ref>