Dissecting PROTAB-mediated degradation of cell surface proteins
Jieyan He1, Tao Sun2, Mengwen Zhang3
1Biochemical and Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.
The FEBS Journal
|August 10, 2026
Summary
Proteolysis-Targeting Antibodies (PROTABs) degrade membrane proteins by linking them to E3 ligases. A HER2-PROTAB rapidly depletes the target protein, primarily via lysosomal degradation, but does not guarantee cell growth inhibition.
Area of Science:
- Biotechnology
- Molecular Biology
- Immunology
Background:
- Antibody-mediated protein degradation is a novel therapeutic strategy.
- Proteolysis-Targeting Antibodies (PROTABs) harness E3 ligases to degrade target proteins.
- The precise mechanisms of PROTAB action require further investigation.
Purpose of the Study:
- To elucidate the mechanism of action of a HER2-targeting PROTAB.
- To investigate ternary complex formation, internalization, ubiquitination, and degradation pathways.
- To assess the correlation between target degradation and cellular response.
Main Methods:
- Utilized a bispecific PROTAB targeting HER2 and ZNRF3.
- Analyzed ternary complex formation, receptor internalization, and ubiquitination.
- Quantified target protein depletion and assessed degradation pathways (lysosomal vs. proteasomal).
- Evaluated the impact of target degradation on cell growth.
Main Results:
- PROTAB induced rapid ternary complex formation and HER2 internalization.
- Achieved ~85% HER2 depletion within 24 hours, predominantly via lysosomal degradation.
- Ubiquitination enhanced but was not essential for internalization.
- ZNRF3 accumulated at the cell surface; PROTAB was recycled.
- Target degradation did not consistently inhibit cell growth.
Conclusions:
- Provided a mechanistic framework for PROTAB function, highlighting lysosomal degradation.
- Demonstrated that ZNRF3 is not codegraded and PROTAB is recycled.
- Emphasized target dependency and cellular context in PROTAB efficacy.
- Informed the design of next-generation antibody-based protein degraders.
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