Identification and structural basis of C-terminal cyclic imides as natural degrons for cereblon
Open accessAbstract
Cereblon (CRBN) is a ubiquitously expressed E3 ligase substrate receptor and a key player in pharmaceutical targeted protein degradation. Despite substantial insight gained into its chemical ligand space that is exploited in small-molecule protein degraders, its cellular role and native mechanism of substrate recognition remained elusive so far. In this communication, we report the discovery of C-terminal aspartimide and aminoglutarimide residues as natural degron motifs that are recognized by CRBN with high specificity. These C-terminal cyclic imides are known to form in ageing proteins as a result of spontaneous chain breaks after an attack of an asparagine or glutamine side chain amide on the adjacent peptide bond, and thereby mark potentially malfunctional protein fragments. In crystal structures, we uncover that these C-terminal cyclic imides are bound in the same fashion as small-molecule CRBN modulators, and that the residues preceding the cyclic terminus contribute to the interaction with a sequence-unspecific backbone hydrogen bonding pattern with strictly conserved residues in CRBN. We postulate that C-terminal aspartimide and aminoglutarimide residues resulting from chain breaks are largely underappreciated protein damages and represent the native degrons of CRBN.
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The underlying principles of molecular glue mechanisms might be rooted in partial mimicry of naturally occurring PPIs at preexisting sites of high PPI propensity, interactions further enhanced by a matching molecular glue.
“Taken together, our findings provide another example that the underlying principles of molecular glue mechanisms might be rooted in the partial mimicry of naturally occurring PPIs at preexisting sites of high PPI propensity, interactions that are further enhanced by a matching molecular glue1,10,11,50–54.”
From Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry (2026) · cites this paper as [11]
Cites
Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN
Sievers, Q. L., Petzold, G., Bunker, R. D., Renneville, A., Słabicki, M., Liddicoat, B. J., Abdulrahman, W., Mikkelsen, T., Ebert, B. L., & Thomä, N. H. (2018) · Science · doi:10.1126/science.aat0572 · Cited by 537 · see citing works
Thalidomide mimics uridine binding to an aromatic cage in cereblon
Hartmann, M. D., Boichenko, I., Coles, M., Zanini, F., Lupas, A. N., & Hernandez Alvarez, B. (2014) · Journal of Structural Biology · doi:10.1016/j.jsb.2014.10.010 · Cited by 83 · see citing works
Self-citationStructural Dynamics of the Cereblon Ligand Binding Domain
Hartmann, M. D., Boichenko, I., Coles, M., Lupas, A. N., & Hernandez Alvarez, B. (2015) · PLOS ONE · doi:10.1371/journal.pone.0128342 · Cited by 31 · see citing works
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Mining the CRBN target space redefines rules for molecular glue-induced neosubstrate recognition
Petzold, G., Gainza, P., Annunziato, S., Lamberto, I., Trenh, P., McAllister, L. A., DeMarco, B., Schwander, L., Bunker, R. D., Zlotosch, M., et al. (2025) · Science · doi:10.1126/science.adt6736 · Cited by 117 · see citing works
Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders
Kroupova, A., Spiteri, V. A., Rutter, Z. J., Furihata, H., Darren, D., Ramachandran, S., Chakraborti, S., Haubrich, K., Pethe, J., Gonzales, D., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52871-9 · Cited by 47 · see citing works
Molecular glue degraders: exciting opportunities for novel drug discovery
Lemaitre, T., Cornu, M., Schwalen, F., Since, M., Kieffer, C., & Voisin-Chiret, A. S. (2024) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2024.2306845 · Cited by 36 · see citing works
From serendipity to strategy: molecular glue degraders in cancer therapeutics
Darling, S., Bajrami, I., & West, S. C. (2025) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2025.2564068 · Cited by 10 · see citing works
“…or asparagine (N) residues. these potentially defective protein fragments are cleared by the cRl4 cRBN complex to prevent their toxic accumulation (Heim et al. 2022; ichikawa et al. 2022). importantly, in terms of iMiD binding, the residual “non-glutarimide” part of the drug (the phthalimide…”
InfluentialCereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry
Annunziato, S., Quan, C., Donckele, E. J., Lamberto, I., Bunker, R. D., Zlotosch, M., Schwander, L., Murthy, A., Wiedmer, L., Staehly, C., et al. (2026) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01738-8 · Cited by 9 · see citing works
“In contrast, the CULT domain appears critical for native and drug-induced CRBN functions, as it harbors the tritryptophan pocket (Trp-cage) that engages cyclic imide degrons 10,11 , as well as its small-molecule mimetic, the glutarimide moiety of lenalidomide-type MGDs 16–18 .”
- Authors
- Heim, C., Spring, A.-K., Kirchgäßner, S., Schwarzer, D., & Hartmann, M. D.
- Affiliations
- NanoTemper Technologies (Germany) (DE)
- Max Planck Institute for Biology (DE)
- University of Tübingen (DE)
- Corresponding author
- Hartmann, Marcus D.
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2022-12
- Volume
- 637
- Pages
- 66-72
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W4308500192
- Cited by
- 51
- References
- 3
- Citations by year
- 2026: 7 · 2025: 20 · 2024: 14 · 2023: 10
- FWCI
- 3.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by)
- Funders
- Paul Scherrer Institut
- Max-Planck-Gesellschaft
- 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
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- cereblon, protein degradation, protein damage, backbone hydrogen bonding, protein crystal structure, targeted protein degradation
- MeSH terms
- Imides, Ligands, Ubiquitin-Protein Ligases, Proteolysis
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