Ubiquitin-like modifier-activating enzyme 5

Definition:

E1-like enzyme which specifically catalyzes the first step in ufmylation. Activates UFM1 by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a UFM1-E1 thioester and free AMP. Activates UFM1 via a trans-binding mechanism, in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer. Trans-binding also promotes stabilization of the UBA5 homodimer, and enhances ATP-binding. Transfer of UFM1 from UBA5 to the E2-like enzyme UFC1 also takes place using a trans mechanism. Ufmylation is involved in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress. Ufmylation is essential for erythroid differentiation of both megakaryocytes and erythrocytes (By similarity).

References:

[1]. Masaaki Komatsu, et al. A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. EMBO J. 2004 May 5;23(9):1977-86. [Content Brief]

[2]. Bayan Mashahreh, et al. Trans-binding of UFM1 to UBA5 stimulates UBA5 homodimerization and ATP binding. FASEB J. 2018 May;32(5):2794-2802. [Content Brief]

[3]. Mei Zheng, et al. UBE1DC1, an ubiquitin-activating enzyme, activates two different ubiquitin-like proteins. J Cell Biochem. 2008 Aug 15;104(6):2324-34. [Content Brief]

[4]. Hee Min Yoo, et al. Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development. Mol Cell. 2014 Oct 23;56(2):261-274. [Content Brief]

[5]. Walaa Oweis, et al. Trans-Binding Mechanism of Ubiquitin-like Protein Activation Revealed by a UBA5-UFM1 Complex. Cell Rep. 2016 Sep 20;16(12):3113-3120. [Content Brief]

[6]. Jin Rui Liang, et al. A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation. Cell. 2020 Mar 19;180(6):1160-1177.e20. [Content Brief]

[7]. Estelle Colin, et al. Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy. Am J Hum Genet. 2016 Sep 1;99(3):695-703. [Content Brief]

[8]. Mikko Muona, et al. Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy. Am J Hum Genet. 2016 Sep 1;99(3):683-694. [Content Brief]

[9]. John-Paul Bacik, et al. Crystal structure of the human ubiquitin-activating enzyme 5 (UBA5) bound to ATP: mechanistic insights into a minimalistic E1 enzyme. J Biol Chem. 2010 Jun 25;285(26):20273-80. [Content Brief]

[10]. Nadine Soudah, et al. An N-Terminal Extension to UBA5 Adenylation Domain Boosts UFM1 Activation: Isoform-Specific Differences in Ubiquitin-like Protein Activation. J Mol Biol. 2019 Feb 1;431(3):463-478. [Content Brief]

[11]. Sabrina Habisov, et al. Structural and Functional Analysis of a Novel Interaction Motif within UFM1-activating Enzyme 5 (UBA5) Required for Binding to Ubiquitin-like Proteins and Ufmylation. J Biol Chem. 2016 Apr 22;291(17):9025-41. [Content Brief]

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