Structure of APP-C991-99 and implications for role of extra-membrane domains in function and oligomerization.
Structure of APP-C991-99 and implications for role of extra-membrane domains in function and oligomerization.
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APP-C991-99 的结构以及膜外结构域在功能和寡聚化中的作用的影响。
DOI：
10.1016/j.bbamem.2018.04.002
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Sugita,Yuji
中科院分区：
文献类型：
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作者：
Pantelopulos,GeorgeA;Straub,JohnE;Thirumalai,D;Sugita,Yuji
淀粉样蛋白前体蛋白APP-C99 （C99）的99个氨基酸c端片段被γ-分泌酶切割形成a β肽，该肽在阿尔茨海默病（AD）的病因学中起关键作用。C99的结构由单个跨膜结构域和细胞内及细胞间结构域组成。虽然跨膜结构域的结构已经被很好地表征，但对其侧翼结构域的结构及其在γ-分泌酶加工C99中的作用知之甚少。为了深入了解全长C99的结构，我们在不同厚度的模型膜中对单体C99进行了REMD模拟。我们发现C99的平衡系综与实验推断的残基插入深度和蛋白质主链化学位移一致。在薄膜中，跨膜域结构与膜外结构状态相关，膜外结构状态之间的相关性降低。跨膜和g37g38铰链角的均值和方差随着膜的变薄而增大。C99的n端形成β链，可能在膜表面播下Aβ聚集的种子，促进淀粉样蛋白的形成。在较厚的膜中，n端形成α-螺旋，与γ-分泌酶的nicastrin结构域相互作用。随着膜的增厚，C99的c端变得更α-螺旋，形成可能适合细胞质蛋白结合的结构，而随着膜的变薄，细胞毒性功能必需的c端残基变得α-螺旋。本文分析的非均匀但离散的膜外结构域状态为C99结构和膜在淀粉样蛋白形成中的作用开辟了新的研究途径。这篇文章是Ayyalusamy Ramamoorthy编辑的题为“细胞膜界面蛋白质聚集和错误折叠”的特刊的一部分。
The 99 amino acid C-terminal fragment of Amyloid Precursor Protein APP-C99 (C99) is cleaved by γ-secretase to form Aβ peptide, which plays a critical role in the etiology of Alzheimer's Disease (AD). The structure of C99 consists of a single transmembrane domain flanked by intra and intercellular domains. While the structure of the transmembrane domain has been well characterized, little is known about the structure of the flanking domains and their role in C99 processing by γ-secretase. To gain insight into the structure of full-length C99, REMD simulations were performed for monomeric C99 in model membranes of varying thickness. We find equilibrium ensembles of C99 from simulation agree with experimentally-inferred residue insertion depths and protein backbone chemical shifts. In thin membranes, the transmembrane domain structure is correlated with extra-membrane structural states and the extra-membrane domain structural states become less correlated to each other. Mean and variance of the transmembrane and G37G38hinge angles are found to increase with thinning membrane. The N-terminus of C99 forms β-strands that may seed aggregation of Aβ on the membrane surface, promoting amyloid formation. In thicker membranes the N-terminus forms α-helices that interact with the nicastrin domain of γ-secretase. The C-terminus of C99 becomes more α-helical as the membrane thickens, forming structures that may be suitable for binding by cytoplasmic proteins, while C-terminal residues essential to cytotoxic function become α-helical as the membrane thins. The heterogeneous but discrete extra-membrane domain states analyzed here open the path to new investigations of the role of C99 structure and membrane in amyloidogenesis. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.