8tqm

Structural highlights

Function

DOA10_YEAST E3 ubiquitin-protein ligase which accepts ubiquitin specifically from endoplasmic reticulum-associated UBC6 and UBC7 E2 ligases, and transfers it to substrates promoting their degradation. Mediates the degradation of a broad range of substrates, inluding endoplasmic reticulum membrane proteins (ERQC), soluble nuclear proteins and soluble cytoplasmic proteins (CytoQC). Component of 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. ERAD-C substrates are ubiquitinated through DOA10 in conjunction with the E2 ubiquitin-conjugating enzymes UBC6 and UBC7-CUE1. Ubiquitinated substrates are then removed to the cytosol via the action of the UFD1-NPL4-CDC48/p97 (UNC) AAA ATPase complex and targeted to the proteasome. Also recognizes the N-terminally acetylated residue of proteins as degradation signal (degron). N-terminally acetylated target proteins include MATALPHA2, TBF1, SLK19, YMR090W, HIS3, HSP104, UBP6 and ARO8.^{[1] [2] [3] [4] [5] [6] [7]}

References

1. ↑ 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
2. ↑ Schuberth C, Buchberger A. Membrane-bound Ubx2 recruits Cdc48 to ubiquitin ligases and their substrates to ensure efficient ER-associated protein degradation. Nat Cell Biol. 2005 Oct;7(10):999-1006. Epub 2005 Sep 18. PMID:16179952 doi:http://dx.doi.org/ncb1299
3. ↑ 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
4. ↑ Ravid T, Kreft SG, Hochstrasser M. Membrane and soluble substrates of the Doa10 ubiquitin ligase are degraded by distinct pathways. EMBO J. 2006 Feb 8;25(3):533-43. Epub 2006 Jan 26. PMID:16437165 doi:http://dx.doi.org/10.1038/sj.emboj.7600946
5. ↑ Deng M, Hochstrasser M. Spatially regulated ubiquitin ligation by an ER/nuclear membrane ligase. Nature. 2006 Oct 19;443(7113):827-31. PMID:17051211 doi:http://dx.doi.org/10.1038/nature05170
6. ↑ Metzger MB, Maurer MJ, Dancy BM, Michaelis S. Degradation of a cytosolic protein requires endoplasmic reticulum-associated degradation machinery. J Biol Chem. 2008 Nov 21;283(47):32302-16. doi: 10.1074/jbc.M806424200. Epub 2008, Sep 23. PMID:18812321 doi:http://dx.doi.org/10.1074/jbc.M806424200
7. ↑ Hwang CS, Shemorry A, Varshavsky A. N-Terminal Acetylation of Cellular Proteins Creates Specific Degradation Signals. Science. 2010 Jan 28. PMID:20110468 doi:http://dx.doi.org/science.1183147