Wang Chuanbo, Jia Mengke, Guan Yvning, Ahmad Sajjad, Mei Jinfei, Ai Hongqi
School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China.
School of Chemistry and Materials Engineering, Engineering Research Center of Biomass Conversion and Pollution Prevention of Anhui Educational Institutions, Fuyang Normal University, Fuyang 236037, P. R. China.
Phys Chem Chem Phys. 2025 Mar 19;27(12):6079-6091. doi: 10.1039/d4cp04813j.
As one of the cell surface receptors, cellular prion protein (PrP) can bind Aβ oligomers (AβOs) and attenuate their neurotoxicity. However, there is still considerable controversy regarding the PrP-AβO interaction, due to the polymorphism and varying size of the AβO species and the void of a full-length PrP 3D structure. To solve this problem, we first complemented the missing residues in the residue-lacking crystal structure of PrP and determined a 3D full-length PrP receptor using "Alphafold2". We subsequently investigated the complexes formed between the PrP receptors-both the full-length and those missing the N-terminus-and a variety of Aβ42 species, including Aβ42 monomers, Aβ oligomers (AβOs) of varying sizes across two phases, as well as Aβ42 fibrils (AβFs), using molecular dynamics simulations. The simulated results indicate that the full-length PrP receptor (23-231) employs a cavity, formed by its amino acid residues 44-51 and AA 95-110 regions, for Aβ42 binding. In contrast, the crystal structure of the PrP receptor, typically lacking the N-terminal sequence (amino acids 23-87), provides a binding cavity composed of amino acids 95-110 and the C-terminal residues 131-161 to bind Aβ42, which is consistent with the diverse experimental outcomes observed ( 2009, (7233), 1128-1132; . 2022, (21), 9264-9270). This underscores the necessity of the novel full-length PrP (PrP23-231) 3D model for replicating experimental findings accurately. Additionally, we utilized both the full-length and truncated models of the PrP receptor to clarify its disruptive effects on the growth of Aβ42 secondary nuclei structures (AβF) and its inhibitory impact on the disordered AβOs across two phases. This work provides molecular-level insights into the PrP-Aβ interaction, facilitating model selection for future experimental studies and identifying molecular targets for designing drugs intended to alleviate the toxicity of Aβ42 oligomers towards the PrP receptor.
作为细胞表面受体之一，细胞朊蛋白（PrP）可与β淀粉样蛋白寡聚体（AβOs）结合并减弱其神经毒性。然而，由于AβO种类的多态性和大小各异，以及缺乏全长PrP的三维结构，关于PrP-AβO相互作用仍存在相当大的争议。为解决这一问题，我们首先补充了PrP缺失残基的晶体结构中缺失的残基，并使用“Alphafold2”确定了三维全长PrP受体。随后，我们利用分子动力学模拟研究了全长PrP受体以及缺失N端的PrP受体与多种Aβ42种类之间形成的复合物，这些Aβ42种类包括Aβ42单体、两个阶段中不同大小的Aβ寡聚体（AβOs）以及Aβ42纤维（AβFs）。模拟结果表明，全长PrP受体（23 - 231）利用其44 - 51位氨基酸残基和95 - 110位氨基酸区域形成的一个腔来结合Aβ42。相比之下，通常缺乏N端序列（23 - 87位氨基酸）的PrP受体晶体结构提供了一个由95 - 110位氨基酸和C端残基131 - 161组成的结合腔来结合Aβ42，这与观察到的各种实验结果一致（2009年，（7233），1128 - 1132；. 2022年，（21），9264 - 9270）。这突出了新型全长PrP（PrP23 - 231）三维模型对于准确复制实验结果的必要性。此外，我们利用PrP受体的全长模型和截短模型来阐明其对Aβ42二级核结构（AβF）生长的破坏作用以及对两个阶段中无序AβOs的抑制作用。这项工作为PrP - Aβ相互作用提供了分子水平的见解，有助于为未来的实验研究选择模型，并确定用于设计旨在减轻Aβ42寡聚体对PrP受体毒性的药物的分子靶点。
