期刊
CURRENT PHARMACEUTICAL DESIGN
卷 15, 期 31, 页码 3644-3655出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/138161209789271799
关键词
Insulin degrading enzyme; insulysin; metallopeptidases; amyloid beta; peptides; Alzheimer; diabetes mellitus type 2; varicella zoster virus
资金
- Agencia Nacional de Promocion Cientifica y Tecnologica [PICT 2005-38009, PICT 2006 2354]
Insulin-degrading enzyme (IDE) or insulysin is a highly conserved Zn2+-dependent endopeptidase with an inverted HxxEH motif. In vivo, IDE contributes to regulate the steady state levels of peripheral insulin and cerebral amyloid beta peptide (A beta) of Alzheimer's disease. In vitro, substrates of IDE include a broad spectrum of peptides with relevant physiological functions such as atrial natriuretic factor, insulin-like growth factor-II, transforming growth factor, alpha,beta-endorphin, amylin or glucagon. The recently solved crystal structures of an inactive IDE mutant bound to four different substrates indicate, in accordance with previous compelling biochemical data, that peptide backbone conformation and size are major determinants of IDE recognition and substrate selectivity. IDE-N and IDE-C halves contribute to substrate binding and may rotate away from each other leading to open and closed conformers that permit or preclude the entry of substrates. Noteworthy, stabilization of substrate beta strands in their IDE-bound form may explain the preference of IDE for peptides with a high tendency to self-assembly as amyloid fibrils. These structural requirements may underlie the capability of some amyloid peptides of forming extremely stable complexes with IDE and raise the possibility of a dead-end chaperone-like function of IDE independent of catalysis. Furthermore, the recent recognition of IDE as a varicella zoster virus receptor and its putative involvement in muscle cell differentiation, steroid receptor signaling or proteasome modulation suggest that IDE is a multi-functional protein with broad and relevant roles in several basic cellular processes. Accordingly, IDE functions, regulation or trafficking may partake in the molecular pathogenesis of major human diseases and become potential targets for therapeutic intervention.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据