Characterizing the transmembrane domains of ADAM10 and BACE1 and the impact of membrane composition.
Characterizing the transmembrane domains of ADAM10 and BACE1 and the impact of membrane composition.
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表征 ADAM10 和 BACE1 的跨膜结构域以及膜组成的影响。
DOI：
10.1016/j.bpj.2023.08.025
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发表时间：
2023
影响因子：
3.4
通讯作者：
Straub,JohnE
中科院分区：
文献类型：
--
作者：
Abraham,ConorB;Xu,Lin;Pantelopulos,GeorgeA;Straub,JohnE
已知β-分泌酶BACE 1和α-分泌酶ADAM 10在阿尔茨海默病的淀粉样级联中竞争性切割淀粉样前体蛋白（APP）。APP被BACE 1切割产生99个残基的C-末端肽（APP-C99），其随后被γ-分泌酶切割以形成淀粉样蛋白-β（Aβ）蛋白，而APP被ADAM 10切割是非淀粉样蛋白原性的。据推测，ADAM 10/APP和BACE 1/APP相互作用是通过液体有序膜结构域内部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征尚不清楚。在这项工作中，我们已经开发和特点的最小同源序列的跨膜结构域的ADAM 10和BACE 1使用多尺度建模方法相结合的温度副本交换和传统的分子动力学模拟的基础上粗粒度Martini2.2和全原子CHARMM 36力场。我们的研究结果表明，膜组成的影响BACE 1和ADAM 10的跨膜结构域的字符，增加了可信度的推测，膜结构域参与阿尔茨海默病的病因。
Theβ-secretase, BACE1, and theα-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 byγ-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.