Structure and membrane orientation of IAPP in its natively amidated form at physiological pH in a membrane environment.
Structure and membrane orientation of IAPP in its natively amidated form at physiological pH in a membrane environment.
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DOI：
10.1016/j.bbamem.2011.06.012
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发表时间：
2011-10
影响因子：
3.4
通讯作者：
Ramamoorthy, Ayyalusamy
中科院分区：
文献类型：
--
作者：
Nanga, Ravi Prakash Reddy;Brender, Jeffrey R.;Vivekanandan, Subramanian;Ramamoorthy, Ayyalusamy
人胰岛淀粉样多肽是一种由胰岛β细胞与胰岛素共表达的激素。由于不清楚的原因，hIAPP在II型糖尿病患者体内聚集形成寡聚体，干扰β细胞功能，最终导致胰岛素产生的损失。细胞膜催化淀粉样蛋白沉积的形成，并通过破坏膜的结构完整性而成为淀粉样蛋白毒性的靶点。因此，目前有相当大的兴趣在膜环境中解决该多肽的三维结构。由于多肽的快速聚集，核磁共振实验不能直接用于脂质双层。为了克服这一困难，我们解决了中性pH下洗涤剂胶束中自然产生的多肽的结构。该结构具有整体扭曲的螺旋基序，7-17和21-28残基呈螺旋构象，Gly 33-Asn 35有310个螺旋。此外，N端和C端螺旋之间的角度被限制为85度。酰胺化形式的人IAPP比游离酸形式的人IAPP螺旋含量更高，这可能对其聚集和膜破坏活性起作用。
Human islet amyloid polypeptide is a hormone coexpressed with insulin by pancreatic beta-cells. For reasons not clearly understood, hIAPP aggregates in type II diabetics to form oligomers that interfere with beta-cell function, eventually leading to the loss of insulin production. The cellular membrane catalyzes the formation of amyloid deposits and is a target of amyloid toxicity through disruption of the membrane’s structural integrity. Therefore, there is considerable current interest in solving the 3D structure of this peptide in a membrane environment. NMR experiments could not be directly utilized in lipid bilayers due to the rapid aggregation of the peptide. To overcome this difficulty, we have solved the structure of the naturally occurring peptide in detergent micelles at a neutral pH. The structure has an overall kinked helix motif, with residues 7–17 and 21–28 in a helical conformation, and with a 310 helix from Gly 33 – Asn 35. In addition, the angle between the N- and C-terminal helices is constrained to 85º. The greater helical content of human IAPP in the amidated versus free acid form is likely to play a role in its aggregation and membrane disruptive activity.
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