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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure and topology of monomeric phospholamban in lipid membranes determined by a hybrid solution and solid-state NMR approach
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Structure and topology of monomeric phospholamban in lipid membranes determined by a hybrid solution and solid-state NMR approach

机译：通过混合溶液和固态NMR方法确定脂质膜中单体磷酸lamban的结构和拓扑

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摘要

Phospholamban (PLN) is an essential regulator of cardiac muscle contractility. The homopentameric assembly of PLN is the reservoir for active monomers that, upon deoligomerization form 1:1 complexes with the sarco(endo)plasmic reticulum Ca~(2+)-ATPase (SERCA), thus modulating the rate of calcium uptake. In lipid bilayers and micelles, monomeric PLN exists in equilibrium between a bent (or resting) T state and a more dynamic (or active) R state. Here, we report the high-resolution structure and topology of the T state of a monomeric PLN mutant in lipid bilayers, using a hybrid of solution and solid-state NMR restraints together with moleeular dynamics simulations in explicit lipid environments. Unlike the previous structural ensemble determined in micelles, this approach gives a complete picture of the PLN monomer structure in a lipid bilayer. This hybrid ensemble exemplifies the tilt, rotation, and depth of membrane insertion, revealing the interaction with the lipids for all protein domains. The N-terminal amphipathic helical domain la (residues 1-16) rests on the surface of the lipid membrane with the hydrophobic face of domain la embedded in the membrane bilayer interior. The helix comprised of domain Ib (residues 23-30) and transmembrane domain II (residues 31-52) traverses the bilayer with a tilt angle of ≈24°. The specific interactions between PLN and lipid membranes may represent an additional regulatory element of its inhibitory function. We propose this hybrid method for the simultaneous determination of structure and topology for membrane proteins with compact folds or proteins whose spatial arrangement is dictated by their specific interactions with lipid bilayers.
机译：Phospholamban（PLN）是心肌收缩力的重要调节剂。 PLN的同五聚体组装是活性单体的储存库，这些活性单体在解聚后与肌质网Ca〜（2 +）-ATPase（SERCA）形成1：1的复合物，从而调节钙的吸收速率。在脂质双层和胶束中，单体PLN处于弯曲（或静止）T状态和动态（或更活跃）R状态之间的平衡状态。在这里，我们报告在脂双层中的单体PLN突变体的T状态的高分辨率结构和拓扑，使用溶液和固态NMR约束的混合以及在明确脂类环境中的分子动力学模拟。与以前在胶束中确定的结构集合不同，此方法可完整显示脂质双层中PLN单体结构。该杂种集合体例证了膜插入的倾斜，旋转和深度，揭示了与所有蛋白质结构域的脂质相互作用。 N末端两亲性螺旋结构域1a（残基1-16）位于脂质膜的表面上，结构域1a的疏水性表面嵌入膜双层内部。由结构域Ib（残基23-30）和跨膜结构域II（残基31-52）组成的螺旋以约24°的倾斜角横穿双层。 PLN和脂质膜之间的特异性相互作用可能代表了其抑制功能的另一个调控元素。我们提出了这种混合方法，用于同时测定具有紧密折叠的膜蛋白或其空间排列由与脂双层的特定相互作用决定的蛋白的结构和拓扑。

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    Nathaniel J. Traaseth; Lei Shi; Raffaello Verardi; Daniel G. Mullen; George Barany; Gianluigi Veglia;

  • 作者单位

    Departments of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455;

    Departments of Chemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455;

    Departments of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455;

    Departments of Chemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455;

    Departments of Chemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455;

    Departments of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455rnDepartments of Chemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    hybrid method; membrane proteins; oriented solid-state NMR; molecular modeling; PISEMA;

    机译：混合法膜蛋白定向固态NMR分子模拟皮斯马;

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