Structural Basis for UFM1 Transfer from UBA5 to UFC1

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Sep 30

PMID 34588452

Citations 12

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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Ichihara Y, Okawa M, Minegishi M, Oizumi H, Yamamoto M, Ohbuchi K Medicines (Basel). 2025; 12(1.

PMID: 39846712 PMC: 11755592. DOI: 10.3390/medicines12010002.

Multifaceted roles of UFMylation in health and disease.

Wang R, Li L, Zhou J, Ran J Acta Pharmacol Sin. 2025; .

PMID: 39775503 DOI: 10.1038/s41401-024-01456-9.

A novel compound heterozygous mutation of UFC1 in a patient with neurodevelopmental disorder.

Han Y, Ge Y, Liu H, Liu L, Xie L, Chen X Genes Genomics. 2024; 46(9):1037-1043.

PMID: 39078589 DOI: 10.1007/s13258-024-01543-5.

Allelic strengths of encephalopathy-associated variants correlate between in vivo and in vitro assays.

Pan X, Alvarez A, Ma M, Lu S, Crawford M, Briere L Elife. 2023; 12.

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Insights into the ISG15 transfer cascade by the UBE1L activating enzyme.

Wallace I, Baek K, Prabu J, Vollrath R, von Gronau S, Schulman B Nat Commun. 2023; 14(1):7970.

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