Adduction of cholesterol 5,6-secosterol aldehyde to membrane-bound myelin basic protein exposes an immunodominant epitope.
Adduction of cholesterol 5,6-secosterol aldehyde to membrane-bound myelin basic protein exposes an immunodominant epitope.
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DOI：
10.1021/bi200109q
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发表时间：
2011-03-29
期刊：
影响因子：
2.9
通讯作者：
Wentworth P Jr
中科院分区：
文献类型：
--
作者：
Cygan NK;Scheinost JC;Butters TD;Wentworth P Jr
中枢神经系统中的髓磷脂降解是多发性硬化症 (MS) 的临床标志。通过将精氨酸脱亚胺化为瓜氨酸，髓磷脂碱性蛋白 (MBP) 的净正电荷减少，已被证明与疾病严重程度密切相关，并与髓磷脂不稳定和神经变性之前并导致自身免疫攻击的缺陷有关。最近，我们发现脂质衍生的醛，例如胆固醇 5,6-仲甾醇 atheronal-A (1a) 和 atheronal-B (1b)，在涉及疏水醛加成赖氨酸侧链的过程中调节某些蛋白质的错误折叠，例如载脂蛋白-B100、β-淀粉样蛋白、α-突触核蛋白以及 κ-和 λ-抗体轻链，导致蛋白质净正电荷损失。在这项研究中，我们发现，在由胞质髓鞘和牛 MBP (bMBP) 中发现的脂质成分组成的大单层囊泡 (cyt-LUV) 中，动脉粥样硬化-A (1a) 或动脉粥样硬化-B (1b) 的存在，导致由抗体结合确定的免疫显性表位 (V86-T98) 表面暴露的动脉粥样硬化浓度依赖性增加。还观察到 bMBP 的其他结构变化，特别是 1a-b 诱导 L36-P50 相对于对照 cyt-LUV 的表面暴露减少，通过抗体结合和 F42-F43 的组织蛋白酶 D 蛋白水解减少来测量。对 1a 和 1b 类似物的结构活性关系研究表明，这两种化合物的醛部分对其对 bMBP 结构的影响至关重要。通过荧光显微镜和动态光散射测定，动脉粥样硬化还导致 bMBP-cyt-LUV 聚集体尺寸减小。这些结果表明，炎症衍生的醛之间形成亚胺，有效降低 MBP 的阳离子性质，可导致 MBP 的结构变化和类似于脱亚胺化的髓磷脂稳定性降低，因此可能是 MS 发病和进展的一个迄今为止未知的促成因素。
Myelin degradation in the CNS is a clinical hallmark of multiple sclerosis (MS). A reduction in the net positive charge of myelin basic protein (MBP) via deimination of arginine to citrulline, has been shown to correlate strongly with disease severity and has been linked to myelin instability and a defect that precedes neurodegeneration and leads to autoimmune attack. Recently, we have shown that lipid-derived aldehydes, such as the cholesterol 5,6-secosterols atheronal-A (1a) and atheronal-B (1b), modulate the misfolding of certain proteins such as apolipoprotein-B100, β-amyloid, α-synuclein, and κ-and λ-antibody light chains in a process involving adduction of the hydrophobic aldehyde to lysine side-chains, resulting in a loss in net positive charge of the protein. In this study we show that the presence of either atheronal-A (1a) or atheronal-B (1b) in large unilamellar vesicles (cyt-LUVs) comprised of the lipid composition found in the cytosolic myelin sheath and bovine MBP (bMBP), leads to an atheronal concentration dependent increase in the surface exposure of the immunodominant epitope (V86-T98) as determined by antibody binding. Other structural changes in bMBP were also observed, specifically 1a–b induces a decrease in the surface exposure of L36-P50 relative to control cyt-LUVs as measured both by antibody binding and by a reduction in cathepsin D proteolysis of F42-F43. Structure activity relationship studies with analogs of 1a and 1b point to the aldehyde moiety of both compounds being critical to their effects on bMBP structure. The atheronals also cause a reduction in the size of the bMBP-cyt-LUV aggregates, as determined by fluorescence microscopy and dynamic light scattering. These results suggest that imine formation between inflammatory-derived aldehydes, that effectively reduces the cationic nature of MBP, can lead to structural changes in MBP and a decrease in myelin stability akin to deimination and as such may be a hitherto unknown contributory aspect to the onset and progression of MS.
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影响因子：
14.8
作者：
Bosco, DA;Fowler, DM;Kelly, JW
通讯作者：
Kelly, JW
影响因子：
2.9
作者：
Homchaudhuri, Lopamudra;Polverini, Eugenia;Boggs, Joan M.
通讯作者：
Boggs, Joan M.
影响因子：
2.9
作者：
CHEIFETZ, S;MOSCARELLO, MA
通讯作者：
MOSCARELLO, MA
影响因子：
6.6
作者：
Mac Millan, SV;Ishiyama, N;Harauz, G
通讯作者：
Harauz, G
DOI：
10.1073/pnas.0405665101
发表时间：
2004-09-14
影响因子：
11.1
作者：
Hu, YF;Doudevski, I;Israelachvili, J
通讯作者：
Israelachvili, J