Structural Basis for Lipid Binding and Function by an Evolutionarily Conserved Protein, Serum Amyloid A
Structural Basis for Lipid Binding and Function by an Evolutionarily Conserved Protein, Serum Amyloid A
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DOI：
10.1016/j.jmb.2020.01.029
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发表时间：
2020-03-27
影响因子：
5.6
通讯作者：
Gursky, Olga
中科院分区：
文献类型：
--
作者：
Frame, Nicholas M.;Kumanan, Meera;Gursky, Olga
血清淀粉样蛋白A （SAA）是一种在炎症期间运输脂质的血浆蛋白。为了探索SAA溶液的构象和脂质结合机制，我们使用了氢-氘交换质谱、脂蛋白重构、氨基酸序列分析和分子动力学模拟。在pH值接近7.4时，脂结合和无脂mSAA1的溶液构象与晶体结构细节一致，但也显示出重要的差异。结果表明，两亲性α -螺旋h1和h3包含一个脂质结合位点，该位点在溶液中部分预形成，在结合脂质时稳定，并表现出脂质诱导的h3折叠。该位点通过SAA低聚物的凹疏水表面隔离极性配体。大量无序/动态的c端区域被推测介导了其他配体的混杂结合。h1-h2连接区域预计会形成一个意想不到的β -发夹，这可能代表早期淀粉样变性中间产物。这些结果有助于为理解SAA与其关键功能配体的相互作用、进化保护以及向淀粉样蛋白的转变奠定结构基础。(C) 2020 Elsevier Ltd.版权所有。
Serum amyloid A (SAA) is a plasma protein that transports lipids during inflammation. To explore SAA solution conformations and lipid-binding mechanism, we used hydrogen-deuterium exchange mass spectrometry, lipoprotein reconstitution, amino acid sequence analysis, and molecular dynamics simulations. Solution conformations of lipid-bound and lipid-free mSAA1 at pH similar to 7.4 agreed in details with the crystal structures but also showed important differences. The results revealed that amphipathic alpha-helices h1 and h3 comprise a lipid-binding site that is partially pre-formed in solution, is stabilized upon binding lipids, and shows lipid-induced folding of h3. This site sequesters apolar ligands via a concave hydrophobic surface in SAA oligomers. The largely disordered/dynamic C-terminal region is conjectured to mediate the promiscuous binding of other ligands. The h1-h2 linker region is predicted to form an unexpected beta-hairpin that may represent an early amyloidogenic intermediate. The results help establish structural underpinnings for understanding SAA interactions with its key functional ligands, its evolutional conservation, and its transition to amyloid. (C) 2020 Elsevier Ltd. All rights reserved.