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Arch Biochem Biophys ; 410(2): 307-16, 2003 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-12573291

RESUMO

Amyloid precursor protein (APP) cleaving enzyme (BACE) is the enzyme responsible for beta-site cleavage of APP, leading to the formation of the amyloid-beta peptide that is thought to be pathogenic in Alzheimer's disease (AD). Hence, BACE is an attractive pharmacological target, and numerous research groups have begun searching for potent and selective inhibitors of this enzyme as a potential mechanism for therapeutic intervention in AD. The mature enzyme is composed of a globular catalytic domain that is N-linked glycosylated in mammalian cells, a single transmembrane helix that anchors the enzyme to an intracellular membrane, and a short C-terminal domain that extends outside the phospholipid bilayer of the membrane. Here we have compared the substrate and active site-directed inhibitor binding properties of several recombinant constructs of human BACE. The constructs studied here address the importance of catalytic domain glycosylation state, inclusion of domains other than the catalytic domain, and incorporation into a membrane bilayer on the interactions of the enzyme active site with peptidic ligands. We find no significant differences in ligand binding properties among these various constructs. These data demonstrate that the nonglycosylated, soluble catalytic domain of BACE faithfully reflects the ligand binding properties of the full-length mature enzyme in its natural membrane environment. Thus, the use of the nonglycosylated, soluble catalytic domain of BACE is appropriate for studies aimed at understanding the determinants of ligand recognition by the enzyme active site.


Assuntos
Ácido Aspártico Endopeptidases/química , Proteínas Recombinantes/química , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Células CHO , Catálise , Domínio Catalítico , Linhagem Celular , Membrana Celular/metabolismo , Cromatografia Líquida de Alta Pressão , Cricetinae , Relação Dose-Resposta a Droga , Drosophila , Endopeptidases , Escherichia coli/metabolismo , Glicosilação , Humanos , Concentração Inibidora 50 , Cinética , Ligantes , Luz , Bicamadas Lipídicas/metabolismo , Peptídeos/química , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/metabolismo , Espalhamento de Radiação , Fatores de Tempo
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