BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal; Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal. Electronic address: https://twitter.com/Antonio27902425.
BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal; Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal. Electronic address: https://twitter.com/GuilhermeGilMo1.
J Mol Biol. 2022 Oct 15;434(19):167791. doi: 10.1016/j.jmb.2022.167791. Epub 2022 Aug 12.
Alzheimer's disease (AD) hallmarks include the aggregation of amyloid-β (Aβ), tau and neuroinflammation promoted by several alarmins. Among these is S100B, a small astrocytic homodimeric protein, upregulated in AD, whose multiple biological activities depend on localization, concentration, and assembly state. S100B was reported to inhibit the aggregation and toxicity of Aβ42 and tau similarly to a holdase-type chaperone. This activity is dependent of Ca-binding, which triggers the exposure of a regulatory binding cleft at the S100B dimer interface with which amyloidogenic clients dynamically interact. Although the dimer prevails, a significant portion of secreted S100B in the human brain occurs as higher order multimers, whose protective functions remain uncharacterized and which we here investigate. Resorting to ThT-monitored aggregation kinetics, we determined that unlike the dimer, tetrameric S100B inhibits Aβ42 aggregation at sub/equimolar ratios, an effect that persists in the absence of Ca binding. Structural analysis revealed that S100B tetramerization spawns a novel extended cleft accommodating an aggregation-prone surface that mediates interactions with monomeric Aβ client via hydrophobic interactions, as corroborated by Bis-ANS fluorescence and docking analysis. Correspondingly, at high ionic strength that reduces solvation and favours hydrophobic contacts, the inhibition of Aβ42 aggregation by tetrameric S100B is 3-fold increased. Interestingly, this extended Ca-independent surface favours Aβ42 as substrate, as tau K18 aggregation is not inhibited by the apo tetramer. Overall, results illustrate a mechanism through which oligomerization of the S100B chaperone fine-tunes anti-aggregation activity and client specificity, highlighting the potential functional relevance of S100B multimers in the regulation of AD proteotoxicity.
阿尔茨海默病（AD）的特征包括淀粉样蛋白-β（Aβ）的聚集、tau 蛋白和由几种警报素促进的神经炎症。其中包括 S100B，一种小的星形胶质细胞同源二聚体蛋白，在 AD 中上调，其多种生物学活性取决于定位、浓度和组装状态。据报道，S100B 抑制 Aβ42 和 tau 的聚集和毒性，类似于热休克蛋白型伴侣。这种活性依赖于 Ca 结合，这触发了 S100B 二聚体界面上调节结合裂缝的暴露，与淀粉样蛋白原客户动态相互作用。尽管二聚体占主导地位，但在人脑中有相当一部分分泌的 S100B 以更高阶的多聚体形式存在，其保护功能仍未被描述，我们在这里对此进行研究。通过 ThT 监测的聚集动力学，我们确定与二聚体不同，四聚体 S100B 以亚/等摩尔比抑制 Aβ42 的聚集，这种效应在没有 Ca 结合的情况下仍然存在。结构分析表明，S100B 的四聚化产生了一个新的扩展裂缝，容纳了一个易于聚集的表面，通过疏水性相互作用介导与单体 Aβ 客户的相互作用，这得到了 Bis-ANS 荧光和对接分析的证实。相应地，在降低溶剂化并有利于疏水性接触的高离子强度下，四聚体 S100B 对 Aβ42 聚集的抑制作用增加了 3 倍。有趣的是，这个扩展的 Ca 独立表面有利于 Aβ42 作为底物，因为 tau K18 聚集不受 apo 四聚体的抑制。总的来说，结果说明了 S100B 伴侣蛋白的寡聚化如何微调其抗聚集活性和客户特异性的机制，突出了 S100B 多聚体在调节 AD 蛋白毒性方面的潜在功能相关性。
