The Two-Hydrophobic Domain Tertiary Structure of Reticulon Proteins Is Critical for Modulation of β-Secretase BACE1
The Two-Hydrophobic Domain Tertiary Structure of Reticulon Proteins Is Critical for Modulation of β-Secretase BACE1
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DOI：
10.1002/jnr.22112
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发表时间：
2009-10-01
影响因子：
4.2
通讯作者：
Araki, Wataru
中科院分区：
文献类型：
--
作者：
Kume, Hideaki;Murayama, Kiyoko S.;Araki, Wataru
β位点淀粉样前体蛋白（APP）裂解酶1（BACE 1）是一种膜结合蛋白酶，对β-淀粉样蛋白（A β）的产生至关重要。考虑到A β积累在阿尔茨海默病（AD）中的关键作用，抑制BACE 1活性可能是治疗AD的可行治疗策略。最近，我们和其他人鉴定了reticulon 3（RTN 3）和reticulon 4-B/C（RTN 4-B/C或Nogo-B/C）作为与BACE 1相互作用并抑制其产生A β的能力的膜蛋白。在这项研究中，我们使用了RTN 3和RTN 4的各种突变体-C和C。elegans RTN研究RTNs调节BACE 1的分子机制。我们发现缺少N-末端或C-末端或环结构域的RTN 3突变体以及缺少与BACE 1结合的C-末端结构域的RTN 4-C突变体与野生型RTN 3和RTN 4-C相似。此外，野生型RTN 3、RTN 4-C和这些RTN突变体的过表达类似地减少了表达瑞典突变APP. C的细胞的A β 40和A β 42分泌。与人RTN同源性低的线虫RTN也与BACE 1相互作用并抑制A β分泌。相反，两个RTN 3突变体含有第一或第二潜在跨膜结构域的缺失和第二跨膜结构域的RTN 3交换突变体结合BACE 1，但不能抑制A β分泌。总的来说，这些结果表明RTN蛋白的两个跨膜结构域的三级结构对于RTN调节BACE 1活性的能力是至关重要的，而N-末端、C-末端和环区域对于该功能不是必需的。(C)2009 Wiley-Liss，Inc.
beta-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a membrane-bound protease that is essential for the production of beta-amyloid protein (A beta). Given the crucial role of A beta accumulation in Alzheimer's disease (AD), inhibition of BACE1 activity may represent a feasible therapeutic strategy in the treatment of AD. Recently, we and others identified reticulon 3 (RTN3) and reticulon 4-B/C (RTN4-B/C or Nogo-B/C) as membrane proteins that interact with BACE1 and inhibit its ability to produce A beta. In this study, we employed various mutants of RTN3 and RTN4-C and C. elegans RTN to investigate the molecular mechanisms by which RTNs regulate BACE1. We found that RTN3 mutants lacking the N-terminal or C-terminal or loop domain as well as a RTN4-C mutant lacking the C-terminal domain bound to BACE1 comparably to wild-type RTN3 and RTN4-C. Furthermore, overexpression of wild-type RTN3, RTN4-C, and these RTN mutants similarly reduced A beta 40 and A beta 42 secretion by cells expressing Swedish mutant APP. C. elegans RTN, which has low homology to human RTNs, also interacted with BACE1 and inhibited A beta secretion. In contrast, two RTN3 mutants containing deletions of the first or second potential transmembrane domains and an RTN3 swap mutant of the second transmembrane domain bound BACE1 but failed to inhibit A beta secretion. Collectively, these results suggest that the two-transmembrane-domain tertiary structure of RTN proteins is critical for the ability of RTNs to modulate BACE1 activity, whereas N-terminal, C-terminal and loop regions are not essential for this function. (C) 2009 Wiley-Liss, Inc.