NEDD8 covalently binds catalytic cysteine of UBA3:NAE1

Stable Identifier
R-HSA-8951648
Type
Reaction
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

NEDD8 is attached via a thioester bond to the catalytic cysteine of its E1 as the first step in its transfer to substrates (Walden et al, 2003). The NEDD8 E1 is a heterodimer consisting of UBA3 and NAE1, and transfers NEDD8 to the E2 enzymes from a 'doubly loaded' state. In the first step, NEDD8 binds to the adenylation site on the NAE1 subunit in conjuction with ATP and Mg2+, generating a covalently modified NEDD8-adenylate conjugate. This conjugation activates the NEDD8 C-terminus for chemical attack by the thiol group of the catalytic cysteine of the UBA3 subunit. Catalysis is likely facilitated by a conformational change in the E1 enzyme. After catalysis, NEDD8 is covalently bound in the E1 catalytic site, leaving the adenylation site free to bind another NEDD8 molecule in the second step, prior to NEDD8 transfer to an E2 enzyme (Walden et al, 2003; Huang et al, 2004; Huang et al, 2005; Huang et al, 2007).

Literature References
PubMed ID Title Journal Year
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
14690597 The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis for selective ubiquitin-like protein activation by an E1

Walden, H, Podgorski, MS, Huang, DT, Miller, DW, Howard, RJ, Minor, DL, Holton, JM, Schulman, BA

Mol. Cell 2003
15694336 Structural basis for recruitment of Ubc12 by an E2 binding domain in NEDD8's E1

Huang, DT, Paydar, A, Zhuang, M, Waddell, MB, Holton, JM, Schulman, BA

Mol. Cell 2005
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
Participants
Participant Of
hasEvent
Catalyst Activity
Catalyst Activity
Title
NEDD8 transferase activity of UBA3:NAE1 [cytosol]
Physical Entity
Activity
Orthologous Events
Authored
Reviewed