8BTL

Crystal structure of a complex between the E2 conjugating enzyme UBE2A and the E3 ligase module from UBR4

Summary for 8BTL

• Entry DOI: 10.2210/pdb8btl/pdb
• Descriptor: cDNA FLJ12511 fis, clone NT2RM2001727, highly similar to Homo sapiens ubiquitin protein ligase E3 component n-recognin 4 (UBR4), mRNA, Ubiquitin conjugating enzyme E2 A, ZINC ION (3 entities in total)
• Functional Keywords: e2 conjugating enzyme, e3 ligase, ubiquitin, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 87705.49

Authors

Virdee, S.,Mabbitt, P.D.,Barnsby-Greer, L. (deposition date: 2022-11-29, release date: 2023-12-13, Last modification date: 2024-04-17)

Primary citation

Barnsby-Greer, L.,Mabbitt, P.D.,Dery, M.A.,Squair, D.R.,Wood, N.T.,Lamoliatte, F.,Lange, S.M.,Virdee, S.
UBE2A and UBE2B are recruited by an atypical E3 ligase module in UBR4.
Nat.Struct.Mol.Biol., 31:351-363, 2024

PubMed Abstract: UBR4 is a 574 kDa E3 ligase (E3) of the N-degron pathway with roles in neurodevelopment, age-associated muscular atrophy and cancer. The catalytic module that carries out ubiquitin (Ub) transfer remains unknown. Here we identify and characterize a distinct E3 module within human UBR4 consisting of a 'hemiRING' zinc finger, a helical-rich UBR zinc-finger interacting (UZI) subdomain, and an N-terminal region that can serve as an affinity factor for the E2 conjugating enzyme (E2). The structure of an E2-E3 complex provides atomic-level insight into the specificity determinants of the hemiRING toward the cognate E2s UBE2A/UBE2B. Via an allosteric mechanism, the UZI subdomain modestly activates the Ub-loaded E2 (E2∼Ub). We propose attenuated activation is complemented by the intrinsically high lysine reactivity of UBE2A, and their cooperation imparts a reactivity profile important for substrate specificity and optimal degradation kinetics. These findings reveal the mechanistic underpinnings of a neuronal N-degron E3, its specific recruitment of UBE2A, and highlight the underappreciated architectural diversity of cross-brace domains with Ub E3 activity.

PubMed: 38182926
DOI: 10.1038/s41594-023-01192-4

Experimental method

X-RAY DIFFRACTION (3.2 Å)