Formation of extramembrane β-strands controls dimerization of transmembrane helices in amyloid precursor protein C99.
Formation of extramembrane β-strands controls dimerization of transmembrane helices in amyloid precursor protein C99.
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DOI：
10.1073/pnas.2212207119
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发表时间：
2022-12-27
影响因子：
11.1
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中科院分区：
文献类型：
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由于跨膜蛋白固有的构象多样性，其内在无序结构域的结构表征具有挑战性。使用全原子分子动力学模拟，我们提供了一个详细的结构表征的构象合奏全长APP-C99蛋白在单体和同源二聚体状态。C99单体的C末端膜外结构域形成稳定亚稳α螺旋的瞬时β链，证实在Aβ寡聚化和胞质信号传导中发挥作用。最重要的是，瞬时β-链的形成影响TM同型二聚体的形成，构成膜外和跨膜结构域之间的长距离通信。这些观察结果强调了在TM蛋白复合物中用于调节细胞信号传导的膜外结构域建模的必要性。淀粉样蛋白前体蛋白（APP-C99）是淀粉样蛋白β（Aβ）的前体，其C端结构域为99个残基，是一种跨膜蛋白，含有N端和C端膜外结构域。使用分子动力学（MD）模拟，我们表明，C99单体的结构系综是最好的描述在数千个国家。C99单体倾向于在C端膜外结构域中形成β链，这解释了在顺磁探针NMR实验中观察到的慢自旋弛豫时间。令人惊讶的是，C99的同源二聚化不仅通过在膜外结构域中形成亚稳β链将构象系综从数千种缩小到几种状态，而且还稳定膜外α螺旋。膜外结构域结构被观察到显着影响同源二聚化基序，导致TM结构域构象的修改。我们的研究为C99蛋白的膜外结构域与TM同源二聚体形成之间的通信提供了原子水平的结构基础。这一发现可以作为一个通用的模型，了解无序的膜外结构域对TM蛋白结构的影响。
Structural characterization of intrinsically disordered protein domains in transmembrane (TM) proteins is challenging due to the inherent conformational diversity. Using all-atom molecular dynamics simulations, we provide a detailed structural characterization of the conformational ensemble of full-length APP-C99 protein in monomeric and homodimeric states. The C-terminal extramembrane domain of C99 monomer forms transient β-strands that stabilize metastable α-helices, conjectured to play a role in Aβ oligomerization and cytosolic signaling. Most importantly, formation of transient β-strands influences TM homodimer formation, constituting long-range communication between the extramembrane and transmembrane domains. These observations emphasize the necessity to model extramembrane domains in TM protein complexes used to regulate cell signaling. The 99-residue C-terminal domain of amyloid precursor protein (APP-C99), precursor to amyloid beta (Aβ), is a transmembrane (TM) protein containing intrinsically disordered N- and C-terminal extramembrane domains. Using molecular dynamics (MD) simulations, we show that the structural ensemble of the C99 monomer is best described in terms of thousands of states. The C99 monomer has a propensity to form β-strand in the C-terminal extramembrane domain, which explains the slow spin relaxation times observed in paramagnetic probe NMR experiments. Surprisingly, homodimerization of C99 not only narrows the conformational ensemble from thousands to a few states through the formation of metastable β-strands in extramembrane domains but also stabilizes extramembrane α-helices. The extramembrane domain structure is observed to dramatically impact the homodimerization motif, resulting in the modification of TM domain conformations. Our study provides an atomic-level structural basis for communication between the extramembrane domains of the C99 protein and TM homodimer formation. This finding could serve as a general model for understanding the influence of disordered extramembrane domains on TM protein structure.
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DOI：
10.1021/acs.jpclett.8b02079
发表时间：
2018-08-02
期刊：
The journal of physical chemistry letters
影响因子：
--
作者：
Caldwell TA;Baoukina S;Brock AT;Oliver RC;Root KT;Krueger JK;Glover KJ;Tieleman DP;Columbus L
通讯作者：
Columbus L
影响因子：
4.4
作者：
Kamiya, Motoshi;Sugita, Yuji
通讯作者：
Sugita, Yuji
DOI：
10.1073/pnas.2002570117
发表时间：
2020-08-18
影响因子：
11.1
作者：
Chakraborty, Debayan;Straub, John E.;Thirumalai, D.
通讯作者：
Thirumalai, D.
影响因子：
16.6
作者：
Dimitrov, Mitko;Alattia, Jean-Rene;Fraering, Patrick C.
通讯作者：
Fraering, Patrick C.
影响因子：
3
作者：
Matsuoka, Daisuke;Kamiya, Motoshi;Sugita, Yuji
通讯作者：
Sugita, Yuji