9QIP

Structure of UBA6-BIRC6 (cluster 4)

Summary for 9QIP

• Entry DOI: 10.2210/pdb9qip/pdb
• Related: 9QGG 9QGI 9QGR 9QGW 9QH5 9QHI 9QIA 9QIC 9QIG 9QII 9QIM 9QIO 9QIP 9QIV
• EMDB information: 53130 53131 53147 53149 53155 53170 53183 53184 53187 53188 53192 53193 53195
• Descriptor: Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6, Ubiquitin-like modifier-activating enzyme 6, INOSITOL HEXAKISPHOSPHATE, ... (4 entities in total)
• Functional Keywords: e1, e2, ligase, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 156252.70

Authors

Riechmann, C.,Elliott, P.R. (deposition date: 2025-03-17, release date: 2025-10-29, Last modification date: 2025-12-17)

Primary citation

Riechmann, C.,Ellison, C.J.,Anderson, J.W.,Hofmann, K.,Sarkies, P.,Elliott, P.R.
UBA6 specificity for ubiquitin E2 conjugating enzymes reveals a priority mechanism of BIRC6.
Nat.Struct.Mol.Biol., 2025

PubMed Abstract: In mammals, ubiquitylation is orchestrated by the canonical ubiquitin-activating E1 enzyme UBA1 and the orthogonal E1 UBA6. Growing evidence underscores the essentiality of both E1s, which differentiate between 29 active ubiquitin-conjugating enzymes (E2s). The mechanisms governing this distinction have remained unclear. Here we establish a framework for ubiquitin E1-E2 specificity. Focusing on UBA6-controlled ubiquitylation cascades, we reveal that BIRC6, a UBA6-exclusive E2, gains priority over all other UBA6-competent E2s, underpinning the functional importance of defined UBA6-BIRC6 ubiquitylation events in regulating cell death, embryogenesis and autophagy. By capturing BIRC6 receiving ubiquitin from UBA6 in different states, we observe BIRC6 engaging with the UBA6 ubiquitin fold domain, driving an exceptionally high-affinity interaction that is modulated by the UBA6 Cys-Cap loop. Using this interaction as a template, we demonstrate how to confer activity between E2s and their noncognate E1, providing a tool to delineate E1-E2-dependent pathways. Lastly, we explain how BIRC6 priority does not lead to inhibition of UBA6, through a bespoke thioester switch mechanism that disengages BIRC6 upon receiving ubiquitin. Our findings propose a concept of hierarchy of E2 activity with cognate E1s, which may explain how ubiquitin E1s can each function with over a dozen E2s and orchestrate E2-specific cellular functions.

PubMed: 41350950
DOI: 10.1038/s41594-025-01717-z

Experimental method

ELECTRON MICROSCOPY (4.15 Å)