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Recognition of the Diglycine C-End Degron by CRL2KLHDC2 Ubiquitin Ligase.

Rusnac DV, Lin HC, Canzani D, Tien KX, Hinds TR, Tsue AF, Bush MF, Yen HS, Zheng N
Mol Cell 72 813-822.e4 (2018)
Related entries: 6do3, 6do4

Cited: 32 times
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Abstract

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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  2. End-Binding E3 Ubiquitin Ligases Enable Protease Signaling. Ravalin M, Basu K, Gestwicki JE, Craik CS. ACS Chem Biol 16 2047-2056 (2021)

Articles - 6do5 mentioned but not cited (2)

  1. Recognition of the Diglycine C-End Degron by CRL2KLHDC2 Ubiquitin Ligase. Rusnac DV, Lin HC, Canzani D, Tien KX, Hinds TR, Tsue AF, Bush MF, Yen HS, Zheng N. Mol Cell 72 813-822.e4 (2018)
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Reviews citing this publication (10)

  1. E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones. Ishida T, Ciulli A. SLAS Discov 26 484-502 (2021)
  2. Cullin-RING Ubiquitin Ligase Regulatory Circuits: A Quarter Century Beyond the F-Box Hypothesis. Harper JW, Schulman BA. Annu Rev Biochem 90 403-429 (2021)
  3. NEDD8 and ubiquitin ligation by cullin-RING E3 ligases. Baek K, Scott DC, Schulman BA. Curr Opin Struct Biol 67 101-109 (2021)
  4. From Selenium Absorption to Selenoprotein Degradation. Ha HY, Alfulaij N, Berry MJ, Seale LA. Biol Trace Elem Res 192 26-37 (2019)
  5. Tying up loose ends: the N-degron and C-degron pathways of protein degradation. Timms RT, Koren I. Biochem Soc Trans 48 1557-1567 (2020)
  6. The Hunt for Degrons of the 26S Proteasome. Ella H, Reiss Y, Ravid T. Biomolecules 9 E230 (2019)
  7. How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini. Sherpa D, Chrustowicz J, Schulman BA. Mol Cell 82 1424-1438 (2022)
  8. The Role of Cullin-RING Ligases in Striated Muscle Development, Function, and Disease. Blondelle J, Biju A, Lange S. Int J Mol Sci 21 E7936 (2020)
  9. Selenoprotein S: A versatile disordered protein. Ghelichkhani F, Gonzalez FA, Kapitonova MA, Schaefer-Ramadan S, Liu J, Cheng R, Rozovsky S. Arch Biochem Biophys 731 109427 (2022)
  10. The trinity of ribosome-associated quality control and stress signaling for proteostasis and neuronal physiology. Park J, Park J, Lee J, Lim C. BMB Rep 54 439-450 (2021)

Articles citing this publication (18)

  1. A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Timms RT, Zhang Z, Rhee DY, Harper JW, Koren I, Elledge SJ. Science 365 eaaw4912 (2019)
  2. Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing. Thrun A, Garzia A, Kigoshi-Tansho Y, Patil PR, Umbaugh CS, Dallinger T, Liu J, Kreger S, Patrizi A, Cox GA, Tuschl T, Joazeiro CAP. Mol Cell 81 2112-2122.e7 (2021)
  3. Molecular basis for ubiquitin ligase CRL2FEM1C-mediated recognition of C-degron. Yan X, Wang X, Li Y, Zhou M, Li Y, Song L, Mi W, Min J, Dong C. Nat Chem Biol 17 263-271 (2021)
  4. The C-degron pathway eliminates mislocalized proteins and products of deubiquitinating enzymes. Yeh CW, Huang WC, Hsu PH, Yeh KH, Wang LC, Hsu PW, Lin HC, Chen YN, Chen SC, Yeang CH, Yen HS. EMBO J 40 e105846 (2021)
  5. Molecular basis for arginine C-terminal degron recognition by Cul2FEM1 E3 ligase. Chen X, Liao S, Makaros Y, Guo Q, Zhu Z, Krizelman R, Dahan K, Tu X, Yao X, Koren I, Xu C. Nat Chem Biol 17 254-262 (2021)
  6. Protein quality control degron-containing substrates are differentially targeted in the cytoplasm and nucleus by ubiquitin ligases. Hickey CM, Breckel C, Zhang M, Theune WC, Hochstrasser M. Genetics 217 1-19 (2021)
  7. Cul5-type Ubiquitin Ligase KLHDC1 Contributes to the Elimination of Truncated SELENOS Produced by Failed UGA/Sec Decoding. Okumura F, Fujiki Y, Oki N, Osaki K, Nishikimi A, Fukui Y, Nakatsukasa K, Kamura T. iScience 23 100970 (2020)
  8. Degronomics: Mapping the Interacting Peptidome of a Ubiquitin Ligase Using an Integrative Mass Spectrometry Strategy. Canzani D, Rusnac DV, Zheng N, Bush MF. Anal Chem 91 12775-12783 (2019)
  9. A C-terminal glutamine recognition mechanism revealed by E3 ligase TRIM7 structures. Liang X, Xiao J, Li X, Liu Y, Lu Y, Wen Y, Li Z, Che X, Ma Y, Zhang X, Zhang Y, Jian D, Wang P, Xuan C, Yu G, Li L, Zhang H. Nat Chem Biol 18 1214-1223 (2022)
  10. C-terminal glutamine acts as a C-degron targeted by E3 ubiquitin ligase TRIM7. Ru Y, Yan X, Zhang B, Song L, Feng Q, Ye C, Zhou Z, Yang Z, Li Y, Zhang Z, Li Q, Mi W, Dong C. Proc Natl Acad Sci U S A 119 e2203218119 (2022)
  11. On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy. Varshavsky A. Proc Natl Acad Sci U S A 116 10773-10782 (2019)
  12. E3 ligase autoinhibition by C-degron mimicry maintains C-degron substrate fidelity. Scott DC, King MT, Baek K, Gee CT, Kalathur R, Li J, Purser N, Nourse A, Chai SC, Vaithiyalingam S, Chen T, Lee RE, Elledge SJ, Kleiger G, Schulman BA. Mol Cell 83 770-786.e9 (2023)
  13. Elucidation of E3 ubiquitin ligase specificity through proteome-wide internal degron mapping. Zhang Z, Sie B, Chang A, Leng Y, Nardone C, Timms RT, Elledge SJ. Mol Cell 83 3377-3392.e6 (2023)
  14. Recognition of the CCT5 di-Glu degron by CRL4DCAF12 is dependent on TRiC assembly. Pla-Prats C, Cavadini S, Kempf G, Thomä NH. EMBO J 42 e112253 (2023)
  15. Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules. Hickey CM, Digianantonio KM, Zimmermann K, Harbin A, Quinn C, Patel A, Gareiss P, Chapman A, Tiberi B, Dobrodziej J, Corradi J, Cacace AM, Langley DR, Békés M. Nat Struct Mol Biol (2024)
  16. Mechanism and evolutionary origins of alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10. Patil PR, Burroughs AM, Misra M, Cerullo F, Costas-Insua C, Hung HC, Dikic I, Aravind L, Joazeiro CAP. Cell Rep 42 113100 (2023)
  17. Molecular basis for C-degron recognition by CRL2APPBP2 ubiquitin ligase. Zhao S, Olmayev-Yaakobov D, Ru W, Li S, Chen X, Zhang J, Yao X, Koren I, Zhang K, Xu C. Proc Natl Acad Sci U S A 120 e2308870120 (2023)
  18. 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, Liu T, Mi W, Yu Y, Dong C. Nat Commun 14 2474 (2023)


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