Recognition of the Diglycine C-End Degron by CRL2KLHDC2 Ubiquitin Ligase
Open accessAbstract
Aberrant proteins can be deleterious to cells and are cleared by the ubiquitin-proteasome system. A group of C-end degrons that are recognized by specific cullin-RING ubiquitin E3 ligases (CRLs) has recently been identified in some of these abnormal polypeptides. Here, we report three crystal structures of a CRL2 substrate receptor, KLHDC2, in complex with the diglycine-ending C-end degrons of two early-terminated selenoproteins and the N-terminal proteolytic fragment of USP1. The E3 recognizes the degron peptides in a similarly coiled conformation and cradles their C-terminal diglycine with a deep surface pocket. By hydrogen bonding with multiple backbone carbonyls of the peptides, KLHDC2 further locks in the otherwise degenerate degrons with a compact interface and unexpected high affinities. Our results reveal the structural mechanism by which KLHDC2 recognizes the simplest C-end degron and suggest a functional necessity of the E3 to tightly maintain the low abundance of its select substrates.
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Low-nanomolar substrate-binding affinities of KLHDC2 are probably dependent on the buried C-terminal carboxyl group.
“Their low-nanomolar substratebinding affinities are probably dependent on the buried C-terminal carboxyl group”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [99]
Crystal structures of KLHDC2 bound to C-terminal diglycine degrons reveal a deep pocket shaped by three tryptophan and three tyrosine residues.
“crystal structures of KLHDC2 bound to C-terminal diglycine degrons have revealed a deep pocket shaped by three tryptophan and three tyrosine residues 99 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [99]
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“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript REAGENT or RESOURCE SOURCE IDENTIFIER pFB-GST-KLHDC2 R236A This paper N/A pFB-GST-KLHDC2 R236E This paper N/A pFB-GST-KLHDC2 R241A This paper N/A pFB-GST-KLHDC2 R241E This paper N/A pFB-GST-KLHDC2 R241K This paper N/A pFB-GST-KLHDC2 R241L…”
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Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules
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Structural Biology of CRL Ubiquitin Ligases
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Self-citationUM171 glues asymmetric CRL3–HDAC1/2 assembly to degrade CoREST corepressors
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Self-citationDegrons: defining the rules of protein degradation
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A C-terminal glutamine recognition mechanism revealed by E3 ligase TRIM7 structures
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Small-Molecule Approaches to Targeted Protein Degradation
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“…5 April 2021 | Volume 13 | Article 673205 3II7 KLHL7 adaptor protein (Canning et al., 2013) 16.26 50.20 6DO5 KLHDC2 adaptor protein (Rusnac et al., 2018) 12.15 46.73 4ASC KBTB5 adaptor protein (Canning et al., 2013) 6.50 43.80 5NKP KLHL3 5.63 43.97 6GY5 KLHL20 adaptor protein (Chen…”
InfluentialMolecular basis for recognition of Gly/N-degrons by CRL2ZYG11B and CRL2ZER1
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Multifaceted N-Degron Recognition and Ubiquitylation by GID/CTLH E3 Ligases
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Targeted kinase degradation via the KLHDC2 ubiquitin E3 ligase
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Drug Discovery Approaches to Target E3 Ligases
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Molecular basis for ubiquitin ligase CRL2FEM1C-mediated recognition of C-degron
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E3 ligase autoinhibition by C-degron mimicry maintains C-degron substrate fidelity
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Selenoprotein S: A versatile disordered protein
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The Hunt for Degrons of the 26S Proteasome
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“Apparently, a deep binding pocket at the surface of KLHDC2, accommodates glycine residues exclusively by excluding amino acid side chains [62].”
BackgroundThe C‐degron pathway eliminates mislocalized proteins and products of deubiquitinating enzymes
Yeh, C., Huang, W., Hsu, P., Yeh, K., Wang, L., Hsu, P. W., Lin, H., Chen, Y., Chen, S., Yeang, C., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020105846 · Cited by 32 · see citing works
Self-citationExpanding the ligand spaces for E3 ligases for the design of protein degraders
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C-terminal amides mark proteins for degradation via SCF–FBXO31
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“Do the proteins in these data align with those that are observed by the authors following oxidative damage?”
Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2
Scott, D. C., Dharuman, S., Griffith, E. C., Chai, S. C., Ronnebaum, J., King, M. T., Tangallapally, R. P., Lee, C., Gee, C. T., Yang, L., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52966-3 · Cited by 28 · see citing works
Recognition of the CCT5 di‐Glu degron by CRL4DCAF12 is dependent on TRiC assembly
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The Role of Cullin-RING Ligases in Striated Muscle Development, Function, and Disease
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C-terminal glutamine acts as a C-degron targeted by E3 ubiquitin ligase TRIM7
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Mechanism of Ψ-Pro/C-degron recognition by the CRL2FEM1B ubiquitin ligase
Chen, X., Raiff, A., Li, S., Guo, Q., Zhang, J., Zhou, H., Timms, R. T., Yao, X., Elledge, S. J., Koren, I., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47890-5 · Cited by 24 · see citing works
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“12 Notably, in the model of apo-full-length KLHDC10, its N terminus, which has Ala at positions 3 and 4, folds back and binds to the same pocket as the Ala-tail peptide (Figure S2).”
InfluentialMolecular basis for C-degron recognition by CRL2 APPBP2 ubiquitin ligase
Zhao, S., Olmayev-Yaakobov, D., Ru, W., Li, S., Chen, X., Zhang, J., Yao, X., Koren, I., Zhang, K., & Xu, C. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2308870120 · Cited by 17 · see citing works
Virtual screening: hope, hype, and the fine line in between
Nada, H., Meanwell, N. A., & Gabr, M. T. (2025) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2025.2458666 · Cited by 18 · see citing works
New PROTAC Designs for Targeted Protein Degradation in 2021–2025: Novel E3 Ligases and Pre-PROTACs
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Exploration of degrons and their ability to mediate targeted protein degradation
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Friend or foe? Reciprocal regulation between E3 ubiquitin ligases and deubiquitinases
Bolhuis, D. L., Emanuele, M. J., & Brown, N. G. (2024) · Biochemical Society Transactions · doi:10.1042/bst20230454 · Cited by 15 · see citing works
Recognition of an Ala-rich C-degron by the E3 ligase Pirh2
Wang, X., Li, Y., Yan, X., Yang, Q., Zhang, B., Zhang, Y., Yuan, X., Jiang, C., Chen, D., Liu, Q., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38173-6 · Cited by 14 · see citing works
A C-Degron Structure-Based Approach for the Development of Ligands Targeting the E3 Ligase TRIM7
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Structural basis for C-degron selectivity across KLHDCX family E3 ubiquitin ligases
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“2d) 34 .”
InfluentialCanzani, D., Rusnac, D.-V., Zheng, N., & Bush, M. F. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.9b02331 · Cited by 11 · see citing works
Self-citationCharacteristics of the Kelch domain containing ( KLHDC ) subfamily and relationships with diseases
Pilcher, C., Buco, P. A. V., Truong, J. Q., Ramsland, P. A., Smeets, M. F. M. A., Walkley, C. R., & Holien, J. K. (2025) · FEBS Letters · doi:10.1002/1873-3468.15108 · Cited by 12 · see citing works
“Emerging research has indicated that some KLHDC subfamily members such as KLHDC2 and KLHDC3 utilise the CRL2 complex to facilitate these previously described steps of ubiquitination [26,30,43,44,52 – 54].”
InfluentialEnd-Binding E3 Ubiquitin Ligases Enable Protease Signaling
Ravalin, M., Basu, K., Gestwicki, J. E., & Craik, C. S. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00621 · Cited by 10 · see citing works
Degrons and degradation signals beyond short linear motifs
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“27,60) (Figs.”
Self-citationYang, L., Wang, Z., Geng, R., Niu, S., Zuo, H., Weng, S., He, J., & Xu, X. (2022) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2022.06.009 · Cited by 8 · see citing works
On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy
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Selenoprotein K at the intersection of cellular pathways
Odunsi, A., Kapitonova, M. A., Woodward, G., Rahmani, E., Ghelichkhani, F., Liu, J., & Rozovsky, S. (2024) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2024.110221 · Cited by 7 · see citing works
C-terminal amides mark proteins for degradation via SCF/FBXO31
Muhar, M., Farnung, J., Hofmann, R., Cernakova, M., Sidiropoulos, N. D., Bode, J. W., & Corn, J. E. (2023) · doi:10.1101/2023.06.29.547030 · Cited by 5 · see citing works
Probing the CRL4DCAF12 interactions with MAGEA3 and CCT5 di-Glu C-terminal degrons
Righetto, G. L., Yin, Y., Duda, D. M., Vu, V., Szewczyk, M. M., Zeng, H., Li, Y., Loppnau, P., Mei, T., Li, Y.-Y., et al. (2024) · PNAS Nexus · doi:10.1093/pnasnexus/pgae153 · Cited by 5 · see citing works
“Various C-terminal “degrons,” transposable degradation causing sequences, have been reported to regulate the stability of many proteins via interactions with Cullin – RING E3 ligases, including KLHDC2, KLHDC3, and KLHDC10, that recognize a C-terminal di-glycine motif (9).”
BackgroundMolecular insights into degron recognition by CRL5ASB7 ubiquitin ligase
Zhou, M., Wang, X., Li, J., Ma, J., Bao, Z., Yan, X., Zhang, B., Liu, T., Yu, Y., Mi, W., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50556-x · Cited by 5 · see citing works
N/C-degron pathways and inhibitor development for PROTAC applications
Wu, Z., Huang, Y., Liu, K., & Min, J. (2023) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2023.194952 · Cited by 5 · see citing works
Ślusarz, M. J., & Lipińska, A. D. (2023) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.26651 · Cited by 4 · see citing works
Selective CDK6 Degradation via the KLHDC2 E3 Ubiquitin Ligase
Jeon, E., Kim, Y., Ahn, H., Martinez, M. J., Hwang, K., Cho, S., Dwyer, B. G., Romero, B. A., Hinshaw, S. M., Gray, N. S., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c02713 · Cited by 4 · see citing works
Decoding Protein–Peptide Interactions Using a Large, Target-Agnostic Yeast Surface Display Library
Hurley, J. D., Shlosman, I., Lakshminarayan, M., Zhao, Z., Hong, Y., Nowak, R. P., Fischer, E. S., & Kruse, A. C. (2025) · ACS Chemical Biology · doi:10.1021/acschembio.5c00265 · Cited by 4 · see citing works
Design of Cytotoxic T Cell Epitopes by Machine Learning of Human Degrons
Truex, N. L., Mohapatra, S., Melo, M. B., Rodriguez, J., Li, N., Abraham, W. D., Sementa, D., Touti, F., Keskin, D. B., Wu, C. J., et al. (2024) · ACS Central Science · doi:10.1021/acscentsci.3c01544 · Cited by 4 · see citing works
Targeted protein degradation by KLHDC2 ligands identified by high-throughput screeningPreprint
Zhou, H., Zhou, T., Yu, W., Liu, L., Ko, Y., Johnson, K. A., Wilson, I. A., Schultz, P. G., & Bollong, M. J. (2025) · eLife · doi:10.7554/elife.106844 · Cited by 4 · see citing works
“Previous work has shown that recognition of the diglycine degron of SelK by KLHDC2 in its Kelch beta propellor domain is characterized by low nanomolar dissociation constants (<10 nM) and with favorable binding kinetics for PROTAC development ( Figure 1A ; Rusnac et al., 2018 ).”
InfluentialTargeted protein degradation by KLHDC2 ligands identified by high-throughput screening
Zhou, H., Zhou, T., Yu, W., Liu, L., Ko, Y., Johnson, K. A., Wilson, I. A., Schultz, P. G., & Bollong, M. J. (2025) · eLife · doi:10.7554/elife.106844.2 · Cited by 3 · see citing works
Minute amounts of helicase-deficient truncated RECQL4 are sufficient for DNA replication
Buco, P., Castillo-Tandazo, W., Chalk, A., Pilcher, C., Holien, J. K., Heierhorst, J., Tan, T. Y., Koren, A., Smeets, M., & Walkley, C. R. (2026) · EMBO Reports · doi:10.1038/s44319-026-00727-2 · Cited by 1 · see citing works
“KLHDC3 is a substrate recognition component of the CRL E3 ubiquitination system (Pilcher et al, 2025; Rusnac et al, 2018; Timms et al, 2023; Yeh et al, 2021; Zhang et al, 2023).”
Small-molecule degron mimetics for targeted protein degradation
Liu, X. (2025) · Essays in Biochemistry · doi:10.1042/ebc20253026 · Cited by 2 · see citing works
Ślusarz, M. J. (2024) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2024.117795 · Cited by 2 · see citing works
Structural Insights Into the Initiation and Elongation of Ubiquitination by Ubr1Preprint
Pan, M., Zheng, Q., Wang, T., Liang, L., Mao, J., Zuo, C., Ding, R., Ai, H., Xie, Y., Si, D., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.12.439291 · Cited by 2 · see citing works
“Purified Ub(1-75)-MesNa (1 μmol, 1 equiv) and Molecule 2 (1.”
MethodInfluentialMycobacterium tuberculosis effector protein PE5 hijacks the host CRL2 ubiquitin ligase complexPreprint
Madduri, B. T. S. A., Vehra, O., Han, A., Radeny, J., Resstel, C., & Bell, S. L. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.11.659056 · Cited by 2 · see citing works
“While KLHDC2 recognizes a C-terminal Gly-166 Gly 24 , KLHDC3 recognizes a C-terminal Arg-X-Arg/Lys/Gln-Gly 25 ; FEM1B/C recognizes a C-terminal Arg, and APPBP2 recognizes a C-terminal Arg-X-X-Gly (Figure 1C) 16,17,26 .”
Luo, S., Liu, X., Wang, X., Liu, H., & Ge, W. (2025) · Journal of Structural Biology · doi:10.1016/j.jsb.2025.108278 · Cited by 1 · see citing works
Buco, P. A. V., Hoque, A., Castillo‐Tandazo, W., Chalk, A. M., Smeets, M. F. M. A., & Walkley, C. R. (2026) · BMC Genomics · doi:10.1186/s12864-026-12574-5 · Cited by 1 · see citing works
“The members have been characterised to varying extents, with KLHDC2 being the most extensively described [17, 20–22].”
Programmable, target-induced fluorogenic CRISPR–tDeg platform for live-cell RNA visualization
Zhong, H., Zhou, J., Qin, F., Zhang, X., & Chen, M. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag279 · Cited by 1 · see citing works
Engler, C., Abriata, L. A., & Bologna, N. G. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag421 · Cited by 1 · see citing works
Coiled-coil scaffolds for Targeted Protein DegradationPreprint
Korona, B., Mylemans, B., Acevedo‐Jake, A. M., Huang, D. T., Edwards, T. A., Wilson, A. J., Woolfson, D. N., & Itzhaki, L. S. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.22.695764 · Cited by 1 · see citing works
Targeted Protein Degradation by KLHDC2 Ligands Identified by High Throughput ScreeningPreprint
Zhou, H., Zhou, T.-L., Yu, W., Liu, L., Ko, Y., Johnson, K. A., Wilson, I. A., Schultz, P. G., & Bollong, M. J. (2025) · eLife · doi:10.7554/elife.106844.1
Deletion of KLHDC3, an E3 ubiquitin ligase complex substrate receptor, leads to obesity in micePreprint
Buco, P. A. V., Hoque, A., Castillo‐Tandazo, W., Chalk, A. M., Smeets, M. F. M. A., & Walkley, C. R. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.05.668783
Targeting the Ubiquitin-Proteasome System in cancer
Spallek, R., McLaughlin, C., & Sapkota, G. P. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-29808-0.00078-9
Selective proteasomal degradation from the Golgi apparatus membranePreprint
Diamantino, J., Murteira, S., Lawo, S., Kaschani, F., Kaiser, M., & Hellerschmied, D. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.04.703791
Molecular basis for C-degron recognition by the SCF Das1 ubiquitin ligasePreprint
Bouchain, M., Varga, J. K., Kong, K.-Y. E., Hofmann, K., Schueler‐Furman, O., & Khmelinskii, A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.13.724490
“…the free C-terminal carboxyl group of a degron, while adjacent residues or pockets accommodate specific degron side chains to enforce sequence selectivity (Rusnac et al., 2018; Scott et al., 2024; Patil et al., 2023; Pla ‐ Prats et al., 2023; Zhao et al., 2021; Yan et al., 2021; Chen et al., 2021).”
Chen, Y., Gao, R., Li, J., Li, R., Wang, X., Tang, X., Wang, X., Wei, Y., Li, L., Ma, Y., et al. (2026) · Protein Science · doi:10.1002/pro.70787
BindingDB (2025) · UC San Diego · doi:10.7270/q2b85dsn
- Authors
- Rusnac, D.-V., Lin, H.-C., Canzani, D., Tien, K. X., Hinds, T. R., Tsue, A. F., Bush, M. F., Yen, H.-C. S., & Zheng, N.
- Affiliations
- National Taiwan University (TW)
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Zheng, Ning
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 72
- Issue
- 5
- Pages
- 813-822.e4
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC6294321
- OpenAlex
- W2902716597
- Cited by
- 93
- References
- 47
- Citations by year
- 2026: 8 · 2025: 19 · 2024: 19 · 2023: 12 · 2022: 7 · 2021: 11 · 2020: 9 · 2019: 8
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute (101-CDA-L05)
- Academia Sinica
- MOST (106-2321-B-001-045)
- NIH (T32GM008268)
- NSF (CHE-1807382)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- diglycine, ubiquitin-proteasome system, substrate recognition, USP1, protein degradation, crystal structure, hydrogen bonding, substrate specificity
- MeSH terms
- Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Amino Acid Sequence, Animals, Antigens, Neoplasm, Binding Sites, Cloning, Molecular, Escherichia coli, Genetic Vectors, Glycylglycine, Humans, Kinetics, Protein Binding, Recombinant Proteins, Substrate Specificity, Gene Expression, Baculoviridae, Crystallography, X-Ray, Spodoptera, Proteasome Endopeptidase Complex, Selenoproteins, Protein Interaction Domains and Motifs, HEK293 Cells, Molecular Docking Simulation, Ubiquitin-Specific Proteases
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