Evidence for ProTα-TLR4/MD-2 binding: molecular dynamics and gravimetric assay studies
Evidence for ProTα-TLR4/MD-2 binding: molecular dynamics and gravimetric assay studies
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DOI：
10.1517/14712598.2015.1005597
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发表时间：
2015-07-01
影响因子：
4.6
通讯作者：
Ueda, Hiroshi
中科院分区：
文献类型：
--
作者：
Omotuyi, Olaposi;Matsunaga, Hayato;Ueda, Hiroshi
目的：在预处理过程中，脂多糖（LPS）选择性地激活TLR 4/MD-2/Toll/IL-1含受体结构域的接头诱导IFN-β（TRIF）途径而不是促炎性髓样分化蛋白-88（MyD 88）/MyD 88-接头样蛋白（MAL）途径。还已知细胞外胸腺素原α（ProT α）在某些疾病状况中选择性地激活TLR 4/MD 2/TRIF-IRF 3途径。本研究采用重量分析法研究ProT alpha/TLR 4/MD-2复合物形成的生物物理学依据，采用分子动力学模拟方法研究其相互作用动力学。通过静电相互作用，全长ProTa（F-ProT α）C端肽（aa 91 - 111）表面上与类似的TLR 4/MD-2相互作用（K-D = 273.36 nm vs 16.07 μ g/ml [LPS]）构象，而F-ProTa通过一个-氨基酸移位-Mosoian结构域（aa-51 - 90）。结论：ProTa通过其C端肽段（aa 91 - 111）与LPS识别的TLR 4/MD-2复合物构象在体外具有生物物理接触。
Objective: During preconditioning, lipopolysaccharide (LPS) selectively activates TLR4/MD-2/Toll/IL-1 receptor-domain-containing adaptor inducing IFN-beta (TRIF) pathway instead of pro-inflammatory myeloid differentiation protein-88 (MyD88)/MyD88-adaptor-like protein (MAL) pathway. Extracellular prothymosin alpha (ProT alpha) is also known to selectively activate the TLR4/MD2/TRIF-IRF3 pathway in certain diseased conditions. In the current study, biophysical evidence for ProT alpha/TLR4/MD-2 complex formation and its interaction dynamics have been studied.Research design and methods: Gravimetric assay was used to investigate ProT alpha/TLR4/MD-2 complex formation while molecular dynamics (MD) simulation was used to study its interaction dynamics.Results: Through electrostatic interaction, full-length ProTa (F-ProT alpha) C-terminal peptide (aa 91 - 111) superficially interacts with similar TLR4/MD-2 (K-D = 273.36 nm vs 16.07 mu g/ml [LPS]) conformation with LPS at an overlapping three-dimensional space while F-ProTa is hinged to the TLR4 scaffold by one-amino acid shift-Mosoian domain (aa-51 - 90). Comparatively, F-ProTa better stabilizes MD-2 metastable states transition and mediates higher TLR4/MD-2 interaction than LPS.Conclusions: ProTa via its C-terminal peptide (aa 91 - 111) exhibits in vitro biophysical contact with TLR4/MD-2 complex conformation recognized by LPS at overlapping LPS-binding positions.