7un6

Complex of UBE2O with NAP1L1Complex of UBE2O with NAP1L1

Structural highlights

7un6 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[UBE2O_HUMAN] E2/E3 hybrid ubiquitin-protein ligase that displays both E2 and E3 ligase activities and mediates monoubiquitination of target proteins (PubMed:23455153, PubMed:24703950). Negatively regulates TRAF6-mediated NF-kappa-B activation independently of its E2 activity (PubMed:23381138). Acts as a positive regulator of BMP7 signaling by mediating monoubiquitination of SMAD6, thereby regulating adipogenesis (PubMed:23455153). Mediates monoubiquitination at different sites of the nuclear localization signal (NLS) of BAP1, leading to cytoplasmic retention of BAP1. Also able to monoubiquitinate the NLS of other chromatin-associated proteins, such as INO80 and CXXC1, affecting their subcellular location (PubMed:24703950). Acts as a regulator of retrograde transport by assisting the TRIM27:MAGEL2 E3 ubiquitin ligase complex to mediate 'Lys-63'-linked ubiquitination of WASHC1, leading to promote endosomal F-actin assembly (PubMed:23452853).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

The E2/E3 enzyme UBE2O ubiquitylates diverse clients to mediate important processes, including targeting unassembled 'orphan' proteins for quality control and clearing ribosomes during erythropoiesis. How quality-control factors, such as UBE2O, select clients on the basis of heterogeneous features is largely unknown. Here, we show that UBE2O client selection is regulated by ubiquitin binding and a cofactor, NAP1L1. Attaching a single ubiquitin onto a client enhances UBE2O binding and multi-mono-ubiquitylation. UBE2O also repurposes the histone chaperone NAP1L1 as an adapter to recruit a subset of clients. Cryo-EM structures of human UBE2O in complex with NAP1L1 reveal a malleable client recruitment interface that is autoinhibited by the intrinsically reactive UBC domain. Adding a ubiquitylated client identifies a distinct ubiquitin-binding SH3-like domain required for client selection. Our findings reveal how multivalency and a feed-forward mechanism drive the selection of protein quality-control clients.

Mechanism of client selection by the protein quality-control factor UBE2O.,Yip MCJ, Sedor SF, Shao S Nat Struct Mol Biol. 2022 Aug;29(8):774-780. doi: 10.1038/s41594-022-00807-6., Epub 2022 Aug 1. PMID:35915257^[5]

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

References

↑ Zhang X, Zhang J, Zhang L, van Dam H, ten Dijke P. UBE2O negatively regulates TRAF6-mediated NF-kappaB activation by inhibiting TRAF6 polyubiquitination. Cell Res. 2013 Mar;23(3):366-77. doi: 10.1038/cr.2013.21. Epub 2013 Feb 5. PMID:23381138 doi:http://dx.doi.org/10.1038/cr.2013.21
↑ Hao YH, Doyle JM, Ramanathan S, Gomez TS, Jia D, Xu M, Chen ZJ, Billadeau DD, Rosen MK, Potts PR. Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination. Cell. 2013 Feb 28;152(5):1051-64. doi: 10.1016/j.cell.2013.01.051. PMID:23452853 doi:http://dx.doi.org/10.1016/j.cell.2013.01.051
↑ Zhang X, Zhang J, Bauer A, Zhang L, Selinger DW, Lu CX, Ten Dijke P. Fine-tuning BMP7 signalling in adipogenesis by UBE2O/E2-230K-mediated monoubiquitination of SMAD6. EMBO J. 2013 Apr 3;32(7):996-1007. doi: 10.1038/emboj.2013.38. Epub 2013 Mar 1. PMID:23455153 doi:http://dx.doi.org/10.1038/emboj.2013.38
↑ Mashtalir N, Daou S, Barbour H, Sen NN, Gagnon J, Hammond-Martel I, Dar HH, Therrien M, Affar el B. Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O. Mol Cell. 2014 May 8;54(3):392-406. doi: 10.1016/j.molcel.2014.03.002. Epub 2014 , Apr 3. PMID:24703950 doi:http://dx.doi.org/10.1016/j.molcel.2014.03.002
↑ Yip MCJ, Sedor SF, Shao S. Mechanism of client selection by the protein quality-control factor UBE2O. Nat Struct Mol Biol. 2022 Aug;29(8):774-780. doi: 10.1038/s41594-022-00807-6., Epub 2022 Aug 1. PMID:35915257 doi:http://dx.doi.org/10.1038/s41594-022-00807-6

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OCA

[1] Zhang X, Zhang J, Zhang L, van Dam H, ten Dijke P. UBE2O negatively regulates TRAF6-mediated NF-kappaB activation by inhibiting TRAF6 polyubiquitination. Cell Res. 2013 Mar;23(3):366-77. doi: 10.1038/cr.2013.21. Epub 2013 Feb 5. PMID:23381138 doi:http://dx.doi.org/10.1038/cr.2013.21

[2] Hao YH, Doyle JM, Ramanathan S, Gomez TS, Jia D, Xu M, Chen ZJ, Billadeau DD, Rosen MK, Potts PR. Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination. Cell. 2013 Feb 28;152(5):1051-64. doi: 10.1016/j.cell.2013.01.051. PMID:23452853 doi:http://dx.doi.org/10.1016/j.cell.2013.01.051

[3] Zhang X, Zhang J, Bauer A, Zhang L, Selinger DW, Lu CX, Ten Dijke P. Fine-tuning BMP7 signalling in adipogenesis by UBE2O/E2-230K-mediated monoubiquitination of SMAD6. EMBO J. 2013 Apr 3;32(7):996-1007. doi: 10.1038/emboj.2013.38. Epub 2013 Mar 1. PMID:23455153 doi:http://dx.doi.org/10.1038/emboj.2013.38

[4] Mashtalir N, Daou S, Barbour H, Sen NN, Gagnon J, Hammond-Martel I, Dar HH, Therrien M, Affar el B. Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O. Mol Cell. 2014 May 8;54(3):392-406. doi: 10.1016/j.molcel.2014.03.002. Epub 2014 , Apr 3. PMID:24703950 doi:http://dx.doi.org/10.1016/j.molcel.2014.03.002

[5] Yip MCJ, Sedor SF, Shao S. Mechanism of client selection by the protein quality-control factor UBE2O. Nat Struct Mol Biol. 2022 Aug;29(8):774-780. doi: 10.1038/s41594-022-00807-6., Epub 2022 Aug 1. PMID:35915257 doi:http://dx.doi.org/10.1038/s41594-022-00807-6

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