Structural and Functional Analysis of a Novel Interaction Motif within UFM1-activating Enzyme 5 (UBA5) Required for Binding to Ubiquitin-like Proteins and Ufmylation

Sabrina Habisov, Jessica Huber, Yoshinobu Ichimura, Masato Akutsu, Natalia Rogova, Frank Loehr, David G McEwan, Terje Johansen, Ivan Dikic, Volker Doetsch, Masaaki Komatsu, Vladimir V Rogov (Lead / Corresponding author), Vladimir Kirkin (Lead / Corresponding author)

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The covalent conjugation of ubiquitin-fold modifier 1 (UFM1) to proteins generates a signal that regulates transcription, response to cell stress, and differentiation. Ufmylation is initiated by ubiquitin-like modifier activating enzyme 5 (UBA5), which activates and transfers UFM1 to ubiquitin-fold modifier-conjugating enzyme 1 (UFC1). The details of the interaction between UFM1 and UBA5 required for UFM1 activation and its downstream transfer are however unclear. In this study, we described and characterized a combined linear LC3-interacting region/UFM1-interacting motif (LIR/UFIM) within the C terminus of UBA5. This single motif ensures that UBA5 binds both UFM1 and light chain 3/γ-aminobutyric acid receptor-associated proteins (LC3/GABARAP), two ubiquitin (Ub)-like proteins. We demonstrated that LIR/UFIM is required for the full biological activity of UBA5 and for the effective transfer of UFM1 onto UFC1 and a downstream protein substrate both in vitro and in cells. Taken together, our study provides important structural and functional insights into the interaction between UBA5 and Ub-like modifiers, improving the understanding of the biology of the ufmylation pathway.

Original languageEnglish
Pages (from-to)9025-9041
Number of pages17
JournalJournal of Biological Chemistry
Volume291
Issue number17
Early online date29 Feb 2016
DOIs
Publication statusPublished - 22 Apr 2016

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    Habisov, S., Huber, J., Ichimura, Y., Akutsu, M., Rogova, N., Loehr, F., McEwan, D. G., Johansen, T., Dikic, I., Doetsch, V., Komatsu, M., Rogov, V. V., & Kirkin, V. (2016). Structural and Functional Analysis of a Novel Interaction Motif within UFM1-activating Enzyme 5 (UBA5) Required for Binding to Ubiquitin-like Proteins and Ufmylation. Journal of Biological Chemistry, 291(17), 9025-9041. https://doi.org/10.1074/jbc.M116.715474