Department of Chemistry, Boston University, Boston, Massachusetts.
Department of Chemistry, Boston University, Boston, Massachusetts; Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Biophys J. 2023 Oct 3;122(19):3999-4010. doi: 10.1016/j.bpj.2023.08.025. Epub 2023 Sep 1.
The β-secretase, BACE1, and the α-secretase, ADAM10, are known to competitively cleave amyloid precursor protein (APP) in the amyloid cascades of Alzheimer's disease. Cleavage of APP by BACE1 produces a 99-residue C-terminal peptide (APP-C99) that is subsequently cleaved by γ-secretase to form amyloid-β (Aβ) protein, whereas cleavage of APP by ADAM10 is nonamyloidogenic. It has been speculated that ADAM10/APP and BACE1/APP interactions are regulated by colocalization within and outside of liquid-ordered membrane domains; however, the mechanism of this regulation and the character of the proteins' transmembrane domains are not well understood. In this work, we have developed and characterized minimal congener sequences for the transmembrane domains of ADAM10 and BACE1 using a multiscale modeling approach combining both temperature replica exchange and conventional molecular dynamics simulations based on the coarse-grained Martini2.2 and all-atom CHARMM36 force fields. Our results show that membrane composition impacts the character of the transmembrane domains of BACE1 and ADAM10, adding credence to the speculation that membrane domains are involved in the etiology of Alzheimer's disease.
β-分泌酶（BACE1）和 α-分泌酶（ADAM10）已知可在阿尔茨海默病的淀粉样蛋白级联反应中竞争性地切割淀粉样前体蛋白（APP）。BACE1 切割 APP 产生 99 个残基的 C 端肽（APP-C99），随后被 γ-分泌酶切割形成淀粉样-β（Aβ）蛋白，而 ADAM10 切割 APP 是非淀粉样的。有人推测，ADAM10/APP 和 BACE1/APP 相互作用是通过在液有序膜域内和外部的共定位来调节的；然而，这种调节的机制和蛋白质跨膜结构域的特性还不是很清楚。在这项工作中，我们使用了一种多尺度建模方法，结合基于粗粒度的 Martini2.2 和全原子 CHARMM36 力场的温度交换和传统分子动力学模拟，为 ADAM10 和 BACE1 的跨膜结构域开发并表征了最小的同系物序列。我们的结果表明，膜组成会影响 BACE1 和 ADAM10 的跨膜结构域的性质，这为膜域参与阿尔茨海默病发病机制的推测提供了依据。
