Structural basis of the 24B3 antibody against the toxic conformer of amyloid β with a turn at positions 22 and 23
Structural basis of the 24B3 antibody against the toxic conformer of amyloid β with a turn at positions 22 and 23
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24B3 抗体的结构基础，该抗体针对 22 和 23 位转角的 β 淀粉样蛋白毒性构象异构体
DOI：
10.1016/j.bbrc.2022.07.010
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发表时间：
2022
影响因子：
3.1
通讯作者：
Irie Kazuhiro
中科院分区：
文献类型：
--
作者：
Irie Yumi;Matsushima Yuka;Kita Akiko;Miki Kunio;Segawa Tatsuya;Maeda Masahiro;Yanagita Ryo C.;Irie Kazuhiro
淀粉样蛋白β蛋白(Aβ)寡聚体参与了阿尔茨海默病(AD)的早期阶段，针对这些有毒寡聚体的抗体可能有助于AD的准确诊断。我们鉴定了Aβ42的有毒构象，在22/23位有转弯，有形成有毒低聚物的倾向。用毒性构象替代物E22P-Aβ9-35免疫小鼠制备的抗体24B3可用于人脑脊液AD的诊断。然而，目前尚不清楚24B3是如何识别脑脊液中野生型β的毒性构象的。在这里，我们报道了24B3Fab与E22P-Aβ11-34络合的晶体结构，在电子密度中观察到其残基16-26，表明24B3识别了22/23位有毒转折的残基。由于24B3只与Aβ42聚合体结合，因此通过酶免疫分析筛选了几个构象受限的Aβ42类似物，它们具有分子内二硫键来模拟有毒的Aβ42聚合体的构象。结果表明，只有F19C、A30HomoC-SS-Aβ42(1)与24B3显著结合。这些数据为其对Aβ42单体的低亲和力和聚集体的选择性提供了结构基础。
Amyloid β-protein (Aβ) oligomers are involved in the early stages of Alzheimer's disease (AD) and antibodies against these toxic oligomers could be useful for accurate diagnosis of AD. We identified the toxic conformer of Aβ42 with a turn at positions 22/23, which has a propensity to form toxic oligomers. The antibody 24B3, developed by immunization of a toxic conformer surrogate E22P-Aβ9-35 in mice, was found to be useful for AD diagnosis using human cerebrospinal fluid (CSF). However, it is not known how 24B3 recognizes the toxic conformation of wild-type Aβ in CSF. Here, we report the crystal structure of 24B3 Fab complexed with E22P-Aβ11-34, whose residues 16–26 were observed in electron densities, suggesting that the residues comprising the toxic turn at positions 22/23 were recognized by 24B3. Since 24B3 bound only to Aβ42 aggregates, several conformationally restricted analogs of Aβ42 with an intramolecular disulfide bond to mimic the conformation of toxic Aβ42 aggregates were screened by enzyme immunoassay. As a result, only F19C,A30homoC-SS-Aβ42 (1) bound significantly to 24B3. These data provide a structural basis for its low affinity to the Aβ42 monomer and selectivity for its aggregate form.