Reactome | Doubly neddylated UBA3:NAE1 binds AcM-UBE2M

Doubly neddylated UBA3:NAE1 binds AcM-UBE2M

Stable Identifier

R-HSA-8951751

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

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Doubly neddylated UBA3:NAE1 binds AcM-UBE2M

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When NAE1:UBA3 is doubly loaded with NEDD8 (one molecule covalently attached to the catalytic cysteine and the other bound in the adenylation site), the E1 enzyme is competent to interact with either of its E2 enzymes, UBE2F and UBE2M (also known as UBC12). Three binding interfaces contribute to the interaction of the E1 and E2 enzymes. When doubly neddylated, the "ubiquitin" folding domain of NAE1 reorients and, in conjunction with the adenylation domain, forms a cryptic E2-binding site. The adenylation domain also makes contact with the amino terminus of either E2 enzyme. UBE2M additionally interacts directly with the NEDD8 molecule covalently attached to the E1 catalytic cysteine (Huang et al, 2004; Huang et al, 2007; reviewed in Enchev et al, 2015). UBE2M is the E2 responsible for transfer of NEDD8 to RBX1-containing E3 ligase complexes, such as those formed with cullins 1, 2, 3 and 4. In contrast, UBE2F is the E2 for the CUL5:RBX2-containing E3 ligase (Huang et al, 2009).

Literature References

PubMed ID	Title	Journal	Year
15361859	A unique E1-E2 interaction required for optimal conjugation of the ubiquitin-like protein NEDD8 Huang, DT, Miller, DW, Mathew, R, Cassell, R, Holton, JM, Roussel, MF, Schulman, BA	Nat. Struct. Mol. Biol.	2004
17220875	Basis for a ubiquitin-like protein thioester switch toggling E1-E2 affinity Huang, DT, Hunt, HW, Zhuang, M, Ohi, MD, Holton, JM, Schulman, BA	Nature	2007
25531226	Protein neddylation: beyond cullin-RING ligases Enchev, RI, Schulman, BA, Peter, M	Nat. Rev. Mol. Cell Biol.	2015
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