Sandbox Reserved 817: Difference between revisions
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= BACE1 = | = '''BACE1''' = | ||
{{STRUCTURE_4ivs| right| PDB=4ivs | SCENE= |CAPTION= Crystal structure of BACE1 with its inhibitor, [[4ivs]] }} | {{STRUCTURE_4ivs| right| PDB=4ivs | SCENE= |CAPTION= Crystal structure of BACE1 with its inhibitor, [[4ivs]] }} | ||
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<Structure load='4ivs' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> | <Structure load='4ivs' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> | ||
The 501 amino acid sequence of BACE1 bears the hallmark features of eukaryotic aspartic proteases of the pepsin family. 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 rotein 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 and several N-linked glycosylation sites | The 501 amino acid sequence of BACE1 bears the hallmark features of eukaryotic aspartic proteases of the pepsin family. 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 rotein 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 and several N-linked glycosylation sites | ||
Structurally, BACE1 belongs to the aspartyl protease family, and contains a bilobal structure forming by an N- and a C-terminal domains [12]. Both N- and C-domains are formed by highly twisted â-sheet structures and each domain contributes an aspartic acid to the catalytic module of the enzyme. It is thus proposed that ligands containing a positive charged moiety might be favorable to counteract the negative charged active site. | |||
== Mechanism == | == Mechanism == | ||