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引用次数: 0
摘要
许多神经退行性疾病都会形成病理性蛋白质聚集,例如阿尔茨海默病患者体内的蛋白质 tau 聚集。清除这些聚集体为治疗这些蛋白质错误折叠疾病提供了一条可能的途径;然而,如何在靶向蛋白质聚集体的同时保留正常细胞功能所需的单体形式,仍然是一项挑战。现在,Benn、Cheng 等人的研究表明,将含 E3 连接酶的蛋白质与目标特异性纳米抗体融合,可以构建 RING-纳米抗体(R-Nb)降解器,从而靶向并选择性地清除聚集成蛋白质聚集体的蛋白质。研究小组推测,纤维状聚集体的结构可能使R-Nb降解因子密集聚集,从而激活降解途径,而单体tau不会诱导R-Nbs聚集,因此不会诱导降解。调整纳米抗体的亲和力也会影响聚类,从而提供另一种介导蛋白质降解的途径。
The formation of pathological protein aggregates occurs in many neurodegenerative diseases, such as the aggregation of the protein tau in patients with Alzheimer’s disease. Removing these aggregates offers a possible route to treat these protein misfolding diseases; however, targeting the aggregated form of a protein while sparing the monomeric form, which is required for normal cellular function, remains a challenge. Now, Benn, Cheng et al. have shown that fusing an E3 ligase-containing protein to a target-specific nanobody enables the construction of RING–nanobody (R-Nb) degraders that can target and selectively remove proteins that have assembled into protein aggregates.
The E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) induces degradation by the clustering and cross-activation of the RING domains of TRIM21. The team hypothesized that the structure of fibrillar aggregates may enable dense clustering of R-Nb degraders and therefore activation of the degradation pathway, whereas monomeric tau would not induce clustering of R-Nbs and therefore would not induce degradation. Tuning the affinity of the nanobody could also affect clustering and thereby provides another route to mediate protein degradation.
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