4jqu

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Crystal structure of Ubc7p in complex with the U7BR of Cue1pCrystal structure of Ubc7p in complex with the U7BR of Cue1p

Structural highlights

4jqu is a 2 chain structure with sequence from Baker's yeast. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:QRI8, UBC7, Ubc7p, YM9711.12, YMR022W (Baker's yeast), CUE1, Cue1p, KIS4, YM8156.06, YMR264W (Baker's yeast)
Activity:Ubiquitin--protein ligase, with EC number 6.3.2.19
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[UBC7_YEAST] Catalyzes the covalent attachment of ubiquitin to other proteins. Functions in degradation of misfolded or regulated proteins localized in the endoplasmic reticulum (ER) lumen or membrane via the ubiquitin-proteasome system. Cognate E2 conjugating enzyme for the DOA10 ubiquitin ligase complex, which is part of the ERAD-C pathway responsible for the rapid degradation of membrane proteins with misfolded cytoplasmic domains, and of the HRD1 ubiquitin ligase complex, which is part of the ERAD-L and ERAD-M pathways responsible for the rapid degradation of soluble lumenal and membrane proteins with misfolded lumenal domains (ERAD-L), or ER-membrane proteins with misfolded transmembrane domains (ERAD-M). Involved in resistance to cadmium poisoning.[1] [2] [3] [4] [5] [6] [7] [CUE1_YEAST] Component of the endoplasmic reticulum-associated protein degradation (ERAD) pathway. Recruits the soluble ubiquitin-conjugating enzyme UBC7 to the cytoplasmic face of the endoplasmic reticulum membrane where it functions in degradation of misfolded or regulated proteins localized in the endoplasmic reticulum (ER) lumen or membrane via the ubiquitin-proteasome system. Targets the E2 conjugating enzyme UBC7 to the DOA10 ubiquitin ligase complex, which is part of the ERAD-C pathway responsible for the rapid degradation of membrane proteins with misfolded cytoplasmic domains, and to the HRD1 ubiquitin ligase complex, which is part of the ERAD-L and ERAD-M pathways responsible for the rapid degradation of soluble lumenal and membrane proteins with misfolded lumenal domains (ERAD-L), or ER-membrane proteins with misfolded transmembrane domains (ERAD-M). Has also a role in cold adaptation, perhaps through effects on sterol biosynthesis.[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]

Publication Abstract from PubMed

Cue1p is an integral component of yeast endoplasmic reticulum (ER)-associated degradation (ERAD) ubiquitin ligase (E3) complexes. It tethers the ERAD ubiquitin-conjugating enzyme (E2), Ubc7p, to the ER and prevents its degradation, and also activates Ubc7p via unknown mechanisms. We have now determined the crystal structure of the Ubc7p-binding region (U7BR) of Cue1p with Ubc7p. The U7BR is a unique E2-binding domain that includes three alpha-helices that interact extensively with the "backside" of Ubc7p. Residues essential for E2 binding are also required for activation of Ubc7p and for ERAD. We establish that the U7BR stimulates both RING-independent and RING-dependent ubiquitin transfer from Ubc7p. Moreover, the U7BR enhances ubiquitin-activating enzyme (E1)-mediated charging of Ubc7p with ubiquitin. This demonstrates that an essential component of E3 complexes can simultaneously bind to E2 and enhance its loading with ubiquitin. These findings provide mechanistic insights into how ubiquitination can be stimulated.

A Structurally Unique E2-Binding Domain Activates Ubiquitination by the ERAD E2, Ubc7p, through Multiple Mechanisms.,Metzger MB, Liang YH, Das R, Mariano J, Li S, Li J, Kostova Z, Byrd RA, Ji X, Weissman AM Mol Cell. 2013 May 23;50(4):516-27. doi: 10.1016/j.molcel.2013.04.004. Epub 2013 , May 9. PMID:23665230[19]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Chen P, Johnson P, Sommer T, Jentsch S, Hochstrasser M. Multiple ubiquitin-conjugating enzymes participate in the in vivo degradation of the yeast MAT alpha 2 repressor. Cell. 1993 Jul 30;74(2):357-69. PMID:8393731
  2. ↑ Biederer T, Volkwein C, Sommer T. Role of Cue1p in ubiquitination and degradation at the ER surface. Science. 1997 Dec 5;278(5344):1806-9. PMID:9388185
  3. ↑ Johnson PR, Swanson R, Rakhilina L, Hochstrasser M. Degradation signal masking by heterodimerization of MATalpha2 and MATa1 blocks their mutual destruction by the ubiquitin-proteasome pathway. Cell. 1998 Jul 24;94(2):217-27. PMID:9695950
  4. ↑ Swanson R, Locher M, Hochstrasser M. A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matalpha2 repressor degradation. Genes Dev. 2001 Oct 15;15(20):2660-74. PMID:11641273 doi:10.1101/gad.933301
  5. ↑ Gardner RG, Shearer AG, Hampton RY. In vivo action of the HRD ubiquitin ligase complex: mechanisms of endoplasmic reticulum quality control and sterol regulation. Mol Cell Biol. 2001 Jul;21(13):4276-91. PMID:11390656 doi:10.1128/MCB.21.13.4276-4291.2001
  6. ↑ Bays NW, Gardner RG, Seelig LP, Joazeiro CA, Hampton RY. Hrd1p/Der3p is a membrane-anchored ubiquitin ligase required for ER-associated degradation. Nat Cell Biol. 2001 Jan;3(1):24-9. PMID:11146622 doi:10.1038/35050524
  7. ↑ Carvalho P, Goder V, Rapoport TA. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell. 2006 Jul 28;126(2):361-73. PMID:16873066 doi:10.1016/j.cell.2006.05.043
  8. ↑ Biederer T, Volkwein C, Sommer T. Role of Cue1p in ubiquitination and degradation at the ER surface. Science. 1997 Dec 5;278(5344):1806-9. PMID:9388185
  9. ↑ Kopski KM, Huffaker TC. Suppressors of the ndc10-2 mutation: a role for the ubiquitin system in Saccharomyces cerevisiae kinetochore function. Genetics. 1997 Oct;147(2):409-20. PMID:9335582
  10. ↑ Lenk U, Sommer T. Ubiquitin-mediated proteolysis of a short-lived regulatory protein depends on its cellular localization. J Biol Chem. 2000 Dec 15;275(50):39403-10. PMID:10991948 doi:http://dx.doi.org/10.1074/jbc.M006949200
  11. ↑ Gilon T, Chomsky O, Kulka RG. Degradation signals recognized by the Ubc6p-Ubc7p ubiquitin-conjugating enzyme pair. Mol Cell Biol. 2000 Oct;20(19):7214-9. PMID:10982838
  12. ↑ Friedlander R, Jarosch E, Urban J, Volkwein C, Sommer T. A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nat Cell Biol. 2000 Jul;2(7):379-84. PMID:10878801 doi:http://dx.doi.org/10.1038/35017001
  13. ↑ Walter J, Urban J, Volkwein C, Sommer T. Sec61p-independent degradation of the tail-anchored ER membrane protein Ubc6p. EMBO J. 2001 Jun 15;20(12):3124-31. PMID:11406589 doi:http://dx.doi.org/10.1093/emboj/20.12.3124
  14. ↑ Gardner RG, Shearer AG, Hampton RY. In vivo action of the HRD ubiquitin ligase complex: mechanisms of endoplasmic reticulum quality control and sterol regulation. Mol Cell Biol. 2001 Jul;21(13):4276-91. PMID:11390656 doi:10.1128/MCB.21.13.4276-4291.2001
  15. ↑ McBratney S, Winey M. Mutant membrane protein of the budding yeast spindle pole body is targeted to the endoplasmic reticulum degradation pathway. Genetics. 2002 Oct;162(2):567-78. PMID:12399372
  16. ↑ Carvalho P, Goder V, Rapoport TA. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell. 2006 Jul 28;126(2):361-73. PMID:16873066 doi:10.1016/j.cell.2006.05.043
  17. ↑ Loertscher J, Larson LL, Matson CK, Parrish ML, Felthauser A, Sturm A, Tachibana C, Bard M, Wright R. Endoplasmic reticulum-associated degradation is required for cold adaptation and regulation of sterol biosynthesis in the yeast Saccharomyces cerevisiae. Eukaryot Cell. 2006 Apr;5(4):712-22. PMID:16607018 doi:http://dx.doi.org/10.1128/EC.5.4.712-722.2006
  18. ↑ Liao M, Faouzi S, Karyakin A, Correia MA. Endoplasmic reticulum-associated degradation of cytochrome P450 CYP3A4 in Saccharomyces cerevisiae: further characterization of cellular participants and structural determinants. Mol Pharmacol. 2006 Jun;69(6):1897-904. Epub 2006 Mar 23. PMID:16556771 doi:http://dx.doi.org/10.1124/mol.105.021816
  19. ↑ Metzger MB, Liang YH, Das R, Mariano J, Li S, Li J, Kostova Z, Byrd RA, Ji X, Weissman AM. A Structurally Unique E2-Binding Domain Activates Ubiquitination by the ERAD E2, Ubc7p, through Multiple Mechanisms. Mol Cell. 2013 May 23;50(4):516-27. doi: 10.1016/j.molcel.2013.04.004. Epub 2013 , May 9. PMID:23665230 doi:10.1016/j.molcel.2013.04.004

4jqu, resolution 1.81Å

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