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Antibodies inhibit hyperactive protein disposal

Emily Ulrich
June 12, 2025

A system of ubiquitin-associated enzymes marks misfolded or needless proteins for degradation to maintain protein homeostasis, but its dysfunction can lead to disease. Hyperactivation of the E3 ubiquitin ligase carboxyl-terminus of Hsp70-interacting protein, or CHIP, is linked to cystic fibrosis, neurodegeneration and cancer. Scientists confront numerous challenges when attempting to inhibit CHIP due to its complex interaction network with E2 ubiquitin-conjugating enzymes and chaperones, so that CHIP can orchestrate ubiquitin transfer to the substrate. CHIP has a dimeric structure and uses its tetratricopeptide repeat, or TPR, domain to bind chaperones and a U-box domain to bind the E2 enzyme.

In a recent Journal of Biological Chemistry article, Dong hee Chung, Emily Connelly and a team at the University of California, San Francisco, used a biopanning platform for screening inhibitors of CHIP. This technique involved a phage display library of fragment antigen-binding antibodies, or Fabs, segments of a full antibody able to penetrate tissues, and rounds of filtering for CHIP binders. The researchers identified six Fabs for further characterization.

The authors performed fluorescence polarization assays to examine whether the Fabs inhibited binding of a model peptide substrate to the CHIP TPR domain. They also assessed the ability of each Fab to inhibit Hsp70 chaperone ubiquitination by CHIP. The Fab 2F1 stood out because of its strong inhibition of both peptide binding and Hsp70 ubiquitination. Using cryogenic electron microscopy, the researchers determined that two 2F1 molecules bind to the CHIP dimer, one at each U-box domain.

The authors suggested that 2F1 and the other Fabs in this study will provide useful tools for scientists to probe the various CHIP domains and substrate interactions. Inhibiting individual aspects of CHIP function will also help scientists gauge the value of CHIP as a potential drug target.

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Emily Ulrich

Emily Ulrich is the ASBMB’s science editor.

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