Decrypting UFMylation: How Proteins Are Modified with UFM1

Banerjee, Sayanika; Kumar, Manoj; Wiener, Reuven

doi:10.3390/biom10101442

Cited by 50 publications

(45 citation statements)

References 79 publications

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“…In addition to SUMOylation, UFMylation is one of the new additions to the UBLs. Similarly, UFMylation has conjugation pathways with a three-step enzymatic reaction and has been linked to several cellular activities [105][106][107]. Since MRE11 UFMylation has just recently been identified, thus data are very limited.…”

Section: Ubiquitination and Ubiquitin-like Modification Of Mre11mentioning

confidence: 99%

Post-Translational Modification of MRE11: Its Implication in DDR and Diseases

Zhang

Jiang

et al. 2021

Genes

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Maintaining genomic stability is vital for cells as well as individual organisms. The meiotic recombination-related gene MRE11 (meiotic recombination 11) is essential for preserving genomic stability through its important roles in the resection of broken DNA ends, DNA damage response (DDR), DNA double-strand breaks (DSBs) repair, and telomere maintenance. The post-translational modifications (PTMs), such as phosphorylation, ubiquitination, and methylation, regulate directly the function of MRE11 and endow MRE11 with capabilities to respond to cellular processes in promptly, precisely, and with more diversified manners. Here in this paper, we focus primarily on the PTMs of MRE11 and their roles in DNA response and repair, maintenance of genomic stability, as well as their association with diseases such as cancer.

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Section: Ubiquitination and Ubiquitin-like Modification Of Mre11mentioning

confidence: 99%

Post-Translational Modification of MRE11: Its Implication in DDR and Diseases

Zhang

Jiang

et al. 2021

Genes

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“…Highly conserved between species except fungi [ 13 ], this small protein modification is structurally similar to Ubiquitin due to the Ub-beta grasp fold but diverges from Ubiquitin and SUMO in terms of sequence, displaying only 21.7% sequence similarity [ 14 , 15 ]. However, the most notable difference is the lack of a C-terminal di-Gly motif, which is replaced by a VG-motif, reminiscent to that of the LC3 family of Ubiquitin-like modifiers.…”

Section: Introductionmentioning

confidence: 99%

Highly Specialized Ubiquitin-Like Modifications: Shedding Light into the UFM1 Enigma

Witting

Mulder

2021

Biomolecules

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Post-translational modification with Ubiquitin-like proteins represents a complex signaling language regulating virtually every cellular process. Among these post-translational modifiers is Ubiquitin-fold modifier (UFM1), which is covalently attached to its substrates through the orchestrated action of a dedicated enzymatic cascade. Originally identified to be involved embryonic development, its biological function remains enigmatic. Recent research reveals that UFM1 regulates a variety of cellular events ranging from DNA repair to autophagy and ER stress response implicating its involvement in a variety of diseases. Given the contribution of UFM1 to numerous pathologies, the enzymes of the UFM1 cascade represent attractive targets for pharmacological inhibition. Here we discuss the current understanding of this cryptic post-translational modification especially its contribution to disease as well as expand on the unmet needs of developing chemical and biochemical tools to dissect its role.

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“…Like other UBLs, it has a low sequence identity to ubiquitin, but shares its specific (β-grasp) fold [ 1 , 2 ]. Unlike other UBLs (except for SUMO), UFM1 has a single C-terminal glycine residue, by which UFM1 gets attached to target proteins using an E1-E2-E3 enzymatic cascade [ 1 , 3 , 4 ]. Initially, the UFM1 precursor protein gets processed by the two specific proteases UfSP1 and UfSP2 to expose the C-terminal glycine residue [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…The exact mechanism of ufmylation and the full range of physiological consequences are not well investigated yet. The key elements of the ufmylation cascade (UBA5, UFC1, UFL1) show significant evolutionary differences to the well characterized enzymatic UBL cascades (e.g., ubiquitin or NEDD8) resulting in a number of structural and functional deviations from the canonical E1-E2-E3 pathways [ 3 , 4 , 28 ]. In contrast to other E1 family members, UBA5 does not display the characteristic domain architecture [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

A Concerted Action of UBA5 C-Terminal Unstructured Regions Is Important for Transfer of Activated UFM1 to UFC1

Wesch

Löhr

Rogova

et al. 2021

IJMS

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Ubiquitin fold modifier 1 (UFM1) is a member of the ubiquitin-like protein family. UFM1 undergoes a cascade of enzymatic reactions including activation by UBA5 (E1), transfer to UFC1 (E2) and selective conjugation to a number of target proteins via UFL1 (E3) enzymes. Despite the importance of ufmylation in a variety of cellular processes and its role in the pathogenicity of many human diseases, the molecular mechanisms of the ufmylation cascade remains unclear. In this study we focused on the biophysical and biochemical characterization of the interaction between UBA5 and UFC1. We explored the hypothesis that the unstructured C-terminal region of UBA5 serves as a regulatory region, controlling cellular localization of the elements of the ufmylation cascade and effective interaction between them. We found that the last 20 residues in UBA5 are pivotal for binding to UFC1 and can accelerate the transfer of UFM1 to UFC1. We solved the structure of a complex of UFC1 and a peptide spanning the last 20 residues of UBA5 by NMR spectroscopy. This structure in combination with additional NMR titration and isothermal titration calorimetry experiments revealed the mechanism of interaction and confirmed the importance of the C-terminal unstructured region in UBA5 for the ufmylation cascade.

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Decrypting UFMylation: How Proteins Are Modified with UFM1

Cited by 50 publications

References 79 publications

Post-Translational Modification of MRE11: Its Implication in DDR and Diseases

Post-Translational Modification of MRE11: Its Implication in DDR and Diseases

Highly Specialized Ubiquitin-Like Modifications: Shedding Light into the UFM1 Enigma

A Concerted Action of UBA5 C-Terminal Unstructured Regions Is Important for Transfer of Activated UFM1 to UFC1

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