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首页> 外文期刊>Biochemistry >Competition between homodimerization and cholesterol binding to the C99 domain of the amyloid precursor protein
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Competition between homodimerization and cholesterol binding to the C99 domain of the amyloid precursor protein

机译：同源化与胆固醇与淀粉样蛋白前体蛋白C99结构域之间的竞争

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摘要

The 99-residue transmembrane C-terminal domain (C99, also known as β-CTF) of the amyloid precursor protein (APP) is the product of the β-secretase cleavage of the full-length APP and is the substrate for γ-secretase cleavage. The latter cleavage releases the amyloid-β polypeptides that are closely associated with Alzheimer's disease. C99 is thought to form homodimers; however, the free energy in favor of dimerization has not previously been quantitated. It was also recently documented that cholesterol forms a 1:1 complex with monomeric C99 in bicelles. Here, the affinities for both homodimerization and cholesterol binding to C99 were measured in bilayered lipid vesicles using both electron paramagnetic resonance (EPR) and F?rster resonance energy transfer (FRET) methods. Homodimerization and cholesterol binding were seen to be competitive processes that center on the transmembrane G_(700)XXXG_(704)XXXG _(708) glycine-zipper motif and adjacent Gly709. On one hand, the observed K_d for cholesterol binding (K_d = 2.7 ± 0.3 mol %) is on the low end of the physiological cholesterol concentration range in mammalian cell membranes. On the other hand, the observed Kd for homodimerization (Kd = 0.47 ± 0.15 mol %) likely exceeds the physiological concentration range for C99. These results suggest that the 1:1 cholesterol/C99 complex will be more highly populated than C99 homodimers under most physiological conditions. These observations are of relevance for understanding the γ-secretase cleavage of C99.
机译：淀粉样蛋白前体蛋白（APP）的99-残基跨膜C-末端域（C99，也称为β-CTF）是全长APP的β分泌酶切割的产物，并且是γ-分泌酶的基材裂解。后者裂解释放与阿尔茨海默病密切相关的淀粉样蛋白-β多肽。 C99被认为形成同态二聚体;然而，先前尚未定量有利于二聚化的自由能。它最近还记录了胆固醇在散哚中与单体C99形成1：1络合物。这里，使用电子顺磁共振（EPR）和Fθ，在双层脂质囊泡中测量同型二聚体和胆固醇结合到C99的亲和力。均二聚体和胆固醇结合被认为是竞争过程，其中心在跨膜G_（700）XXXG_（704）XXXG _（708）甘氨酸 - 拉链基序和相邻的GLY709上。一方面，对于胆固醇结合（K_D = 2.7±0.3mol％）观察到的K_D位于哺乳动物细胞膜的生理胆固醇浓度范围的低端。另一方面，观察到的均二聚体（Kd = 0.47±0.15mol％）可能超过C99的生理浓度范围。这些结果表明，在大多数生理条件下，1：1胆固醇/ C99复合物将比C99同源体更高度填充。这些观察结果对于了解C99的γ-分泌酶切割有关。

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  • 来源
    《Biochemistry》 |2013年第30期|共14页
  • 作者

    Song Y.; Hustedt E.J.; Brandon S.; Sanders C.R.;

  • 作者单位

    Department of Biochemistry Center for Structural Biology Vanderbilt University School of Medicine Nashville TN 37232 United States;

    Department of Molecular Physiology and Biophysics Vanderbilt University School of Medicine Nashville TN 37232 United States;

    Department of Molecular Physiology and Biophysics Vanderbilt University School of Medicine Nashville TN 37232 United States;

    Department of Biochemistry Center for Structural Biology Vanderbilt University School of Medicine Nashville TN 37232 United States;

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  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

    Competition; between; protein;

    机译：竞争;之间;蛋白质;

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