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A Peptide Binder of E3 Ligase Adaptor SPOP Disrupts Oncogenic SPOP‐Protein Interactions in Kidney Cancer Cells
Author(s) -
Wang Zhen,
Zhang Hao,
Chen Baoen,
Ouyang Sisheng,
Zheng Tong,
Zhou Ran,
Dong Ze,
Huang Yue,
Zhang Tao,
Jiang Hualiang,
Gan Jianhua,
Luo Cheng,
Yang CaiGuang
Publication year - 2021
Publication title -
chinese journal of chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.28
H-Index - 41
eISSN - 1614-7065
pISSN - 1001-604X
DOI - 10.1002/cjoc.202000462
Subject(s) - chemistry , signal transducing adaptor protein , ubiquitin ligase , druggability , peptide , pten , microbiology and biotechnology , ubiquitin , cancer research , biochemistry , biology , signal transduction , pi3k/akt/mtor pathway , gene
Main observation and conclusion The E3 ligase adaptor SPOP, overexpressed in the nucleus but frequently dislocated into the cytoplasm in all clear cell Renal Cell Carcinomas (ccRCC), serves as a regulatory hub to promote kidney cancer through the ubiquitination and degradation of multiple downstream cancer proteins. Recently, our identification of a selective small‐molecule inhibitor of the SPOP‐phosphatase and tensin homolog (PTEN) interaction has demonstrated that the oncogenic SPOP‐protein interaction would be a druggable target specific to ccRCC therapy. To our knowledge, this is the first time such a small‐molecule inhibitor has been developed. Herein, we have identified a peptide binder for the SPOP‐MATH domain that disrupts the oncogenic SPOP‐protein interactions in kidney cancer cells. Computational design and biophysical characterization yielded peptide Pep38 that binds to the MATH domain of SPOP and competes on PTEN‐binding to SPOP in vitro . The X‐ray complex structure reveals that the peptide binder features the following combination: one, a mimic of the native peptide binder and two, an additional β‐strand motif in sequence, which could contribute to increased binding affinity. In order to improve cellular permeability, we fused Pep38 with the delivery peptide TAT to prepare peptide TAT38, which inhibits the endogenous substrate binding to SPOP and suppresses the proliferation of the ccRCC cells. Our identification of the peptide inhibitors for SPOP‐protein interactions provides further validation that the oncogenic SPOP‐signaling pathway in ccRCC could be a druggable target specifically applicable to the therapy of kidney cancers.