Targeting endogenous proteins for degradation through the affinity-directed protein missile system
Open accessAbstract
Targeted proteolysis of endogenous proteins is desirable as a research toolkit and in therapeutics. CRISPR/Cas9-mediated gene knockouts are irreversible and often not feasible for many genes. Similarly, RNA interference approaches necessitate prolonged treatments, can lead to incomplete knockdowns and are often associated with off-target effects. Targeted proteolysis can overcome these limitations. In this report, we describe an affinity-directed protein missile (AdPROM) system that harbours the von Hippel–Lindau (VHL) protein, the substrate receptor of the Cullin2 (CUL2) E3 ligase complex, tethered to polypeptide binders that selectively bind and recruit endogenous target proteins to the CUL2-E3 ligase complex for ubiquitination and proteasomal degradation. By using synthetic monobodies that selectively bind the protein tyrosine phosphatase SHP2 and a camelid-derived VHH nanobody that selectively binds the human ASC protein, we demonstrate highly efficient AdPROM-mediated degradation of endogenous SHP2 and ASC in human cell lines. We show that AdPROM-mediated loss of SHP2 in cells impacts SHP2 biology. This study demonstrates for the first time that small polypeptide binders that selectively recognize endogenous target proteins can be exploited for AdPROM-mediated destruction of the target proteins.
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AdPROM combines the endogenous CUL2 CRL machinery with high-affinity polypeptide binders for target protein recognition.
“Recent data from our own laboratory described a novel and efficient proteolytic system that combines the endogenous cullin 2 (CUL2) CRL machinery, with high-affinity polypeptide binders for target protein recognition [18, 19].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [19]
AdPROM showed robust degradation of endogenous ASC and SHP2 proteins in a whole host of human cancer cell lines.
“By fusing VHL with the VHH domain nanobodies recognizing the inflammasomal protein ASC [48], or by fusing VHL to either of the two monobodies that specifically bind the tyrosine phosphatase SHP2 [42], we showed robust degradation of endogenous ASC and SHP2 proteins, respectively, in a whole host of human cancer cell lines [19].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [19]
Nanobody-based technologies such as AdPROM can rapidly inform whether a specific E3 ligase is a suitable candidate.
“In this context, nanobody-based technologies such as AdPROM can rapidly inform whether a specific E3 ligase is a suitable candidate [19].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [19]
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- Authors
- Fulcher, L. J., Hutchinson, L. D., Macartney, T. J., Turnbull, C., & Sapkota, G. P.
- Affiliations
- MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
- Corresponding author
- Sapkota, Gopal P.
- Venue
- Open Biology
- Publisher
- The Royal Society
- Published
- 2017-05
- Volume
- 7
- Issue
- 5
- Pages
- 170066
- ISSN
- 2046-2441 (ISSN-L)
- PMC
- PMC5451546
- OpenAlex
- W2612257694
- Cited by
- 79
- References
- 43
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 14 · 2023: 9 · 2022: 6 · 2021: 4 · 2020: 16 · 2019: 9 · 2018: 7 · 2017: 3
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Open Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Medical Research Council (MC_UU_12016/3)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- targeted proteolysis, von Hippel-Lindau protein, ubiquitination, proteasomal degradation, SHP2, ASC, VHH nanobodies, protein tyrosine phosphatase
- MeSH terms
- A549 Cells, Humans, Blotting, Western, Tumor Suppressor Proteins, RNA Interference, Cullin Proteins, Cell Line, Tumor, Proteasome Endopeptidase Complex, Von Hippel-Lindau Tumor Suppressor Protein, CARD Signaling Adaptor Proteins, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Ubiquitination, Gene Knock-In Techniques, Proteolysis
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