9YLB

Cryo-EM structure of single-loaded human UBA6-UBE2Z/FAT10(a) adenylate complex.

Summary for 9YLB

• Entry DOI: 10.2210/pdb9ylb/pdb
• EMDB information: 73079
• Descriptor: Ubiquitin-like modifier-activating enzyme 6, Ubiquitin-conjugating enzyme E2 Z, Ubiquitin D, ... (5 entities in total)
• Functional Keywords: e1 e2 enzymes, transferase, transferase-ligase complex, transferase/ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 163782.46

Authors

Jia, L.,Ruben, E.A.,Nayak, D.,Bury, P.S.,Nayak, A.,Wasmuth, E.V.,Olsen, S.K. (deposition date: 2025-10-08, release date: 2026-08-12)

Primary citation

Nayak, D.,Jia, L.,Dos Santos Bury, P.,Ruben, E.A.,Shukla, A.,Nayak, A.,Stratton, C.M.,Ebadi, P.,Cho, H.,Tumanova, A.A.,Varughese, J.T.,Yuan, L.,Gao, F.,Cano, K.E.,Davies, C.,Sung, P.,Gack, M.U.,Wasmuth, E.V.,Olsen, S.K.
Cryo-EM structures of UBA6 reveal mechanisms of E1-E2 specificity and dual FAT10/ubiquitin thioester transfer.
Nat Commun, 17:-, 2026

PubMed Abstract: UBA1 and UBA6 define parallel ubiquitin (Ub) activation systems that perform non-overlapping roles in Ub and ubiquitin-like protein (Ubl) signaling. Whereas UBA1 supports the canonical Ub pathway, UBA6 also activates the Ubl FAT10, linking Ub signaling to immune-regulated proteostasis. In addition to selective Ub/Ubl activation, UBA1 and UBA6 engage distinct sets of E2s, yet how these enzymes achieve selective E2 engagement has remained unclear. Using chemical trapping and high-resolution cryo-EM, we determine four structures of UBA6-E2 complexes representing the thioester-transfer step with either FAT10 or Ub, revealing how this E1 distinguishes its cognate partners. UBA6 achieves E2 specificity through coordinated contributions of the UFD and SCCH domains, a dual-domain mechanism that contrasts with the UFD-dominated selectivity of UBA1. The structures further show that an existing inositol hexakisphosphate (InsP₆)-binding site, unique to UBA6, stabilizes an expanded SCCH cleft that pre-organizes the enzyme for selective engagement of UBA6-specific E2s. These findings define principles for E1-E2 recognition and identify InsP₆ as a cofactor shaping specificity within the Ub-like conjugation network.

PubMed: 41764162
DOI: 10.1038/s41467-026-69882-3

Experimental method

ELECTRON MICROSCOPY (3.24 Å)