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<p>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.</p>

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Cryo-EM structures of UBA6 reveal mechanisms of E1–E2 specificity and dual FAT10/ubiquitin thioester transfer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月28日

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  • Digant Nayak,
  • Lijia Jia,
  • Priscila dos Santos Bury,
  • Eliza A. Ruben,
  • Ankita Shukla,
  • Anindita Nayak,
  • Caleb M. Stratton,
  • Pirouz Ebadi,
  • Hee Cho,
  • Anna A. Tumanova,
  • Joyce T. Varughese,
  • Lingmin Yuan,
  • Fei Gao,
  • Kristin E. Cano,
  • Christopher Davies,
  • Patrick Sung,
  • Michaela U. Gack,
  • Elizabeth V. Wasmuth,
  • Shaun K. Olsen

摘要

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.