{"title":"Anti-aggregate activity","authors":"Russell Johnson","doi":"10.1038/s41589-024-01745-8","DOIUrl":null,"url":null,"abstract":"<p>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.</p><p>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.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":12.9000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature chemical biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41589-024-01745-8","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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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