Structural basis for UFM1 transfer from UBA5 to UFC1

Manoj Kumar, Prasanth Padala, Jamal Fahoum, Fouad Hassouna, Tomer Tsaban, Guy Zoltsman, Sayanika Banerjee, Einav Cohen-Kfir, Moshe Dessau, Rina Rosenzweig, Michail N. Isupov, Ora Schueler-Furman, Reuven Wiener*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Ufmylation is a post-translational modification essential for regulating key cellular processes. A three-enzyme cascade involving E1, E2 and E3 is required for UFM1 attachment to target proteins. How UBA5 (E1) and UFC1 (E2) cooperatively activate and transfer UFM1 is still unclear. Here, we present the crystal structure of UFC1 bound to the C-terminus of UBA5, revealing how UBA5 interacts with UFC1 via a short linear sequence, not observed in other E1-E2 complexes. We find that UBA5 has a region outside the adenylation domain that is dispensable for UFC1 binding but critical for UFM1 transfer. This region moves next to UFC1’s active site Cys and compensates for a missing loop in UFC1, which exists in other E2s and is needed for the transfer. Overall, our findings advance the understanding of UFM1’s conjugation machinery and may serve as a basis for the development of ufmylation inhibitors.

Original languageAmerican English
Article number5708
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - 29 Sep 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Fingerprint

Dive into the research topics of 'Structural basis for UFM1 transfer from UBA5 to UFC1'. Together they form a unique fingerprint.

Cite this