Collagen I Weakly Interacts with the β-Sheets of β2-Microglobulin and Enhances Conformational Exchange To Induce Amyloid Formation
Collagen I Weakly Interacts with the β-Sheets of β2-Microglobulin and Enhances Conformational Exchange To Induce Amyloid Formation
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DOI：
10.1021/jacs.9b10421
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发表时间：
2020-01-22
影响因子：
15
通讯作者：
Baum, Jean
中科院分区：
文献类型：
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作者：
Hoop, Cody L.;Zhu, Jie;Baum, Jean
淀粉样蛋白的发生在蛋白质功能和病理上都具有重要意义。折叠的球状蛋白的淀粉样蛋白的形成通常是由部分或完全展开开始的。然而，对于在天然环境中稳定的蛋白质，这种展开事件是如何触发的还不是很清楚。长期血液透析患者关节中免疫球蛋白β(2)-微球蛋白(β(2)m)积聚到淀粉样斑块中是透析相关淀粉样变性(DRA)的标志。虽然β(2)m在体外不能在近中性的pH条件下形成淀粉样蛋白，但β(2)m沉积到关节间隙的定位表明，局部细胞外基质(ECM)蛋白，特别是胶原蛋白，在促进淀粉样蛋白形成方面发挥了作用。事实上，已经观察到胶原和其他细胞外基质成分促进β(2)m淀粉样蛋白的形成，但复合体的大小和各向异性，加上这些相互作用的低亲和力，限制了这些分子对淀粉样蛋白促进机制的原子水平的阐明(S)。使用唯一探测大分子量复合体中弱相互作用的溶液核磁共振方法，我们能够绘制I型胶原在β(2)m上的结合界面，并检测I型胶原诱导的β(2)m主干上的Mu S-ms的时间尺度动力学。通过结合溶液核磁共振弛豫方法和N-15暗态交换饱和转移实验，我们提出了一个模型，在该模型中，弱的、多峰的胶原I-β(2)m相互作用促进了与少量淀粉样蛋白活性物种的交换，以诱导纤维形成。结果描绘了环境的密切作用，将无害的蛋白质转换为淀粉样蛋白活性状态，使淀粉样蛋白沉积在DRA中的定位合理化。
Amyloidogenesis is significant in both protein function and pathology. Amyloid formation of folded, globular proteins is commonly initiated by partial or complete unfolding. However, how this unfolding event is triggered for proteins that are otherwise stable in their native environments is not well understood. The accumulation of the immunoglobulin protein beta(2)-microglobulin (beta(2)m) into amyloid plaques in the joints of long-term hemodialysis patients is the hallmark of dialysis-related amyloidosis (DRA). While beta(2)m does not form amyloid unassisted near neutral pH in vitro, the localization of beta(2)m deposits to joint spaces suggests a role for the local extracellular matrix (ECM) proteins, specifically collagens, in promoting amyloid formation. Indeed, collagen and other ECM components have been observed to facilitate beta(2)m amyloid formation, but the large size and anisotropy of the complex, combined with the low affinity of these interactions, have limited atomic-level elucidation of the amyloid-promoting mechanism(s) by these molecules. Using solution NMR approaches that uniquely probe weak interactions in large molecular weight complexes, we are able to map the binding interfaces on beta(2)m for collagen I and detect collagen I-induced mu s-ms time-scale dynamics in the beta(2)m backbone. By combining solution NMR relaxation methods and N-15-dark-state exchange saturation transfer experiments, we propose a model in which weak, multimodal collagen I-beta(2)m interactions promote exchange with a minor population of amyloid-competent species to induce fibrillogenesis. The results portray the intimate role of the environment in switching an innocuous protein into an amyloid-competent state, rationalizing the localization of amyloid deposits in DRA.