9T7V
Structure of LRRC58-EloB/C-CDO1 in complex with NEDD8-CUL5-RBX2-ARIH2-Ub
Summary for 9T7V
| Entry DOI | 10.2210/pdb9t7v/pdb |
| EMDB information | 55658 |
| Descriptor | Cysteine dioxygenase type 1, FE (III) ION, 5-azanylpentan-2-one, ... (12 entities in total) |
| Functional Keywords | cullin, e3 ligase, ubiquitin, ligase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 9 |
| Total formula weight | 268003.05 |
| Authors | |
| Primary citation | Andree, G.A.,Stier, L.J.,Schmiederer, K.,Thielen, A.S.,Schmid, L.,Maiwald, S.A.,Gottemukkala, K.V.,Du, J.,von Gronau, S.,Strasser, C.,Muller, J.,Henneberg, L.T.,Guyot, C.,Kleiger, G.,Mann, M.,Murray, P.J.,Schulman, B.A. Cysteine availability tunes ubiquitin signaling via inverse stability of LRRC58 E3 ligase and its substrate CDO1. Nat Commun, 17:-, 2026 Cited by PubMed Abstract: Cellular responses to amino acid fluctuations often hinge on ubiquitin-mediated control of metabolic enzymes, yet the underlying E3 ligase pathways remain poorly defined. Using quantitative proteomics and active cullin-RING ligase (CRL) profiling, we identify LRRC58 as a cysteine-responsive substrate receptor whose stability increases sharply under cysteine starvation. Proteomics reveals an inverse relationship between LRRC58 and the metabolic enzyme cysteine dioxygenase 1 (CDO1), suggesting a cysteine-linked regulatory axis. Biochemical reconstitution and cryo-EM structures show that LRRC58 forms an active CUL2- or CUL5-based CRL that selectively positions CDO1 for ubiquitylation at Lys8. Disease mutant versions of CDO1 mapping to the LRRC58 interface and impaired for the endogenous ubiquitylation pathway were degraded through orthogonal targeting by a VHL-based degrader. Together, our proteomics-guided discovery pipeline, cellular stability studies, and structural analyses uncover a metabolically-tuned LRRC58-CDO1 pathway that links cysteine availability to selective proteasomal turnover, reveals principles of metabolite-regulated CRL activity, and showcases mechanisms distinguishing endogenous and targeted protein degradation. PubMed: 42098103DOI: 10.1038/s41467-026-72524-3 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.95 Å) |
Structure validation
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