9r1p
From Proteopedia
Crystal structure of STUB1 complexed with a compound molecule
Structural highlights
DiseaseCHIP_HUMAN Cerebellar ataxia - hypogonadism. The disease is caused by mutations affecting the gene represented in this entry. FunctionCHIP_HUMAN E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation. Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. Ubiquitinates NOS1 in concert with Hsp70 and Hsp40. Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90. Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation. Mediates polyubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB-degradation by the proteasome. Mediates polyubiquitination of CYP3A4. Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedTargeted protein degraders hold potential as therapeutic agents to target conventionally 'undruggable' proteins. Here, we develop a high-throughput screen, DEath FUSion Escaper (DEFUSE), to identify small-molecule protein degraders. By conjugating the protein of interest to a fast-acting triggerable death protein, this approach translates target protein degradation into a cell survival phenotype to illustrate the presence of degraders. Using this method, we discovered a small molecule (SKPer1) that triggers degradation of the oncoprotein SKP2 and specifically kills SKP2-expressing cancer cells. Mechanistically, SKPer1 acts as an induced-proximity degrader by inducing interaction between SKP2 and an E3 ligase, STUB1, resulting in SKP2 ubiquitination and degradation. SKPer1 exhibits substantial tumour suppression with good safety profiles in vivo. We further show that a sequence of ten amino acids from SKP2 can serve as a versatile degradation tag. A rapid imaging-based screen for induced-proximity degraders identifies a potent degrader of oncoprotein SKP2.,Chu Y, Chen S, Yang M, Chen Y, Fang H, Huang P, Xie Y, Sun C, Chen Y, Zhang B, Li L, Mu H, Song D, Cheng W, Wang C, Jiang W, Xu X, He Z, Chen S, Liu M, Ma J, Yang M, Cao J, Gao J, Shen J, Zhang L, Bai Y, Liu Z, Chen J, Dai S, Zeng YA, Zhao Y, Zhou H, Chen C, Ru H, Tan L, Chi X, Wang F, Gao D, Lin M, Deng X, Jiang H Nat Biotechnol. 2025 Sep 10. doi: 10.1038/s41587-025-02793-8. PMID:40931108[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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