Reactome | NEDD8:AcM-UBE2M binds CRL2 E3 ubiquitin ligase complex

NEDD8:AcM-UBE2M binds CRL2 E3 ubiquitin ligase complex

Stable Identifier

R-HSA-8952625

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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NEDD8:AcM-UBE2M binds CRL2 E3 ubiquitin ligase complex

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UBE2M is the E2 ubiquitin ligase for CRL complexes containing cullin 1, 2, 3 and 4 (Huang et al, 2009; Monda et al, 2013). Interaction between UBE2M and the CUL2 E3 complex is facilitated by a DCUN1D (also known as DCNL) scaffold protein, of which there are 5 in human cells (Kim et al, 2008; Kurz et al, 2008; Meyer-Schaller et al, 2009; Monda et al, 2013; Keuss et al, 2016). DCUN1D proteins interact with higher affinity to the N-terminally acetylated forms of UBE2F and UBE2M (Scott et al, 2011; Monda et al, 2013). Although each of the 5 DCUN1D proteins appears to interact with most cullin subtypes, specificity may arise through differences in expression and localization, and DCUN1D3 may play a specialized role in sequestering CRL E3 ligase complexes at the cell membrane (Monda et al, 2013; Keuss et al, 2016; Meyer-Schaller et al, 2009; Huang et al, 2014; reviewed in Enchev et al, 2103). Although in this pathway, COMMD proteins and DCUN1D are shown acting sequentially in the activation of the CRL E3 ligase complex, the relationship between these protein families is not totally clear, as DCUN1D proteins have been identified in complexes that also contain the inhibitor CAND1 (Kim et al, 2008; Huang et al, 2014).
Target specificity of the CRL2 complex is directed by the nature of the F box substrate recognition protein. The best characterized CRL2 F-box protein is the von Hippel-Lindau (VHL) tumor suppressor, which targets the alpha subunit of hypoxia inducible factor (HIFalpha), among other substrates (reviewed in Cai and Yang, 2016). Another example is CRL1/HRD1 that has been reported to target NFE2L2 for degradation in liver (Wu et al, 2014). CRL2 complexes are hijacked by a number of viruses, including adenovirus, Epstein-Barr virus and HPV, among others. This redirects the ubiquitin ligase complex to target host proteins and in this way promotes viral propagation (reviewed in Mahon et al, 2014).

Literature References

PubMed ID	Title	Journal	Year
24636985	Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis Wu, T, Zhao, F, Gao, B, Tan, C, Yagishita, N, Nakajima, T, Wong, PK, Chapman, E, Fang, D, Zhang, DD	Genes Dev	2014
18206966	Dcn1 functions as a scaffold-type E3 ligase for cullin neddylation Kurz, T, Chou, YC, Willems, AR, Meyer-Schaller, N, Hecht, ML, Tyers, M, Peter, M, Sicheri, F	Mol. Cell	2008
19617556	The human Dcn1-like protein DCNL3 promotes Cul3 neddylation at membranes Meyer-Schaller, N, Chou, YC, Sumara, I, Martin, DD, Kurz, T, Katheder, N, Hofmann, K, Berthiaume, LG, Sicheri, F, Peter, M	Proc. Natl. Acad. Sci. U.S.A.	2009
18826954	SCCRO (DCUN1D1) is an essential component of the E3 complex for neddylation Kim, AY, Bommeljé, CC, Lee, BE, Yonekawa, Y, Choi, L, Morris, LG, Huang, G, Kaufman, A, Ryan, RJ, Hao, B, Ramanathan, Y, Singh, B	J. Biol. Chem.	2008
21940857	N-terminal acetylation acts as an avidity enhancer within an interconnected multiprotein complex Scott, DC, Monda, JK, Bennett, EJ, Harper, JW, Schulman, BA	Science	2011
19250909	E2-RING expansion of the NEDD8 cascade confers specificity to cullin modification Huang, DT, Ayrault, O, Hunt, HW, Taherbhoy, AM, Duda, DM, Scott, DC, Borg, LA, Neale, G, Murray, PJ, Roussel, MF, Schulman, BA	Mol. Cell	2009
23201271	Structural conservation of distinctive N-terminal acetylation-dependent interactions across a family of mammalian NEDD8 ligation enzymes Monda, JK, Scott, DC, Miller, DJ, Lydeard, J, King, D, Harper, JW, Bennett, EJ, Schulman, BA	Structure	2013
23401859	DCNL1 functions as a substrate sensor and activator of cullin 2-RING ligase Heir, P, Sufan, RI, Greer, SN, Poon, BP, Lee, JE, Ohh, M	Mol. Cell. Biol.	2013
25314029	Cullin E3 ligases and their rewiring by viral factors Mahon, C, Krogan, NJ, Craik, CS, Pick, E	Biomolecules	2014
25531226	Protein neddylation: beyond cullin-RING ligases Enchev, RI, Schulman, BA, Peter, M	Nat. Rev. Mol. Cell Biol.	2015
27222660	The structure and regulation of Cullin 2 based E3 ubiquitin ligases and their biological functions Cai, W, Yang, H	Cell Div	2016
25349211	SCCRO3 (DCUN1D3) antagonizes the neddylation and oncogenic activity of SCCRO (DCUN1D1) Huang, G, Stock, C, Bommeljé, CC, Weeda, VB, Shah, K, Bains, S, Buss, E, Shaha, M, Rechler, W, Ramanathan, SY, Singh, B	J. Biol. Chem.	2014
26906416	Characterization of the mammalian family of DCN-type NEDD8 E3 ligases Keuss, MJ, Thomas, Y, Mcarthur, R, Wood, NT, Knebel, A, Kurz, T	J. Cell. Sci.	2016