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.

病理性蛋白质聚集体的形成发生在许多神经退行性疾病中，例如阿尔茨海默病患者体内 tau 蛋白的聚集。去除这些聚集物为治疗这些蛋白质错误折叠疾病提供了一种可能的途径；然而，靶向蛋白质的聚集形式，同时保留正常细胞功能所需的单体形式，仍然是一个挑战。现在，Benn、Cheng 等人。研究表明，将含有 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) 降解剂，该降解剂可以靶向并选择性去除已组装成蛋白质聚集体的蛋白质。

E3 泛素连接酶三联基序蛋白 21 (TRIM21) 通过 TRIM21 RING 结构域的聚集和交叉激活来诱导降解。研究小组假设，纤维状聚集体的结构可能使 R-Nb 降解剂密集聚集，从而激活降解途径，而单体 tau 不会诱导 R-Nb 聚集，因此不会诱导降解。调整纳米抗体的亲和力也可能影响聚类，从而提供另一种介导蛋白质降解的途径。