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首页> 外文期刊>Biochemistry >Conformational Dynamics of the Human Islet Amyloid Polypeptide in a Membrane Environment: Toward the Aggregation Prone Form
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Conformational Dynamics of the Human Islet Amyloid Polypeptide in a Membrane Environment: Toward the Aggregation Prone Form

机译：在膜环境中人类胰岛淀粉样多肽的构象动力学：倾向于聚集形式。

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Human islet amyloid polypeptide (hIAPP) is a 37-residue peptide hormone, which upon misfolding changes from the physiologically active monomer into pathological amyloid fibril aggregates in the pancreas of type 2 diabetes mellitus patients. During this process, the insulin-producing pancreatic beta-cells are damaged; however, the underlying mechanism of this mode of cytotoxicity remains elusive. It is known that anionic lipids accelerate amyloid fibril formation, implicating the importance of the cellular membrane in the process, and that a pH close to the level in the beta-cell secretory granules (pH 5.5) inhibits amyloid fibril formation. Using all-atom molecular dynamics simulations, we have investigated the membrane-asociated monomer state of a-helical hIAPP, analyzed specific interactions of hIAPP with a mixed anionic-zwitterionic lipid membrane and examined the influence of pH on the structure and dynamics of hIAPP and its interaction with the membrane. We find that hIAPP primarily interacts with the membrane by forming favorable interactions between anionic lipids and the positively charged residues in the N-terminal part of the peptide. Rationalizing experimental findings, the simulations show that the N-terminal part of the peptide interacts with the membrane in the lipid headgroup region. At neutral pH, the C-terminal part of the peptide, which contains the residues that initiate fibril formation, displays a highly "dynamic, unfolded state, which interacts with the membrane significantly less than the N-terminal part. Such an unfolded form can be proposed to contribute to the acceleration of fibril formation. At low pH, protonation of His18 mediates a stronger interaction of the C-terminal part with the membrane, resulting in the immobilization of the C-terminal part on the membrane surface that might constitute a mechanism by which low pH inhibits fibril formation.
机译：人胰岛淀粉样蛋白多肽（hIAPP）是37个残基的肽激素，在2型糖尿病患者的胰腺中，其从生理活性单体的折叠错误折叠为病理性淀粉样蛋白原纤维聚集体。在此过程中，产生胰岛素的胰岛β细胞被破坏;然而，这种细胞毒性模式的潜在机制仍然难以捉摸。已知阴离子脂质加速淀粉样蛋白原纤维形成，这暗示了细胞膜在该过程中的重要性，并且pH接近β细胞分泌颗粒中的水平（pH 5.5）抑制淀粉样蛋白原纤维形成。使用全原子分子动力学模拟，我们研究了α-螺旋hIAPP的膜缔合单体状态，分析了hIAPP与阴离子-两性离子脂质膜的相互作用，并考察了pH对hIAPP的结构和动力学的影响。它与膜的相互作用。我们发现，hIAPP主要通过在阴离子脂质和该肽N端部分的带正电荷的残基之间形成有利的相互作用而与膜相互作用。合理化实验结果，模拟结果表明，肽的N末端部分与脂质头基区域的膜相互作用。在中性pH值下，肽的C末端部分（包含引发原纤维形成的残基）表现出高度的“动态”折叠状态，与膜的相互作用明显少于N末端部分。这种展开形式可以在低pH值下，His18的质子化介导了C末端部分与膜的更强相互作用，导致C末端部分固定在膜表面上，这可能构成了原纤维的形成。低pH抑制原纤维形成的机理。

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