Pabis, Marta; Termathe, Martin; Ravichandran, Keerthiraju E; Kienast, Sandra D.; Krutyhołowa, Rościsław; Sokołowski, Mikołaj; Jankowska, Urszula; Grudnik, Przemysław; Leidel, Sebastian A.; Glatt, Sebastian (2020). Molecular basis for the bifunctional Uba4–Urm1 sulfur‐relay system in tRNA thiolation and ubiquitin‐like conjugation. The EMBO journal, 39(19) EMBO Press 10.15252/embj.2020105087
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The chemical modification of tRNA bases by sulfur is crucial to tune translation and to optimize protein synthesis. In eukaryotes, the ubiquitin-related modifier 1 (Urm1) pathway is responsible for the synthesis of 2-thiolated wobble uridine (U34 ). During the key step of the modification cascade, the E1-like activating enzyme ubiquitin-like protein activator 4 (Uba4) first adenylates and thiocarboxylates the C-terminus of its substrate Urm1. Subsequently, activated thiocarboxylated Urm1 (Urm1-COSH) can serve as a sulfur donor for specific tRNA thiolases or participate in ubiquitin-like conjugation reactions. Structural and mechanistic details of Uba4 and Urm1 have remained elusive but are key to understand the evolutionary branch point between ubiquitin-like proteins (UBL) and sulfur-relay systems. Here, we report the crystal structures of full-length Uba4 and its heterodimeric complex with its substrate Urm1. We show how the two domains of Uba4 orchestrate recognition, binding, and thiocarboxylation of the C-terminus of Urm1. Finally, we uncover how the catalytic domains of Uba4 communicate efficiently during the reaction cycle and identify a mechanism that enables Uba4 to protect itself against self-conjugation with its own product, namely activated Urm1-COSH.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP) |
UniBE Contributor: |
Kienast, Sandra Denise, Leidel, Sebastian Andreas |
Subjects: |
500 Science > 570 Life sciences; biology 500 Science > 540 Chemistry |
ISSN: |
0261-4189 |
Publisher: |
EMBO Press |
Language: |
English |
Submitter: |
Christina Schüpbach |
Date Deposited: |
03 Feb 2021 15:02 |
Last Modified: |
05 Dec 2022 15:45 |
Publisher DOI: |
10.15252/embj.2020105087 |
BORIS DOI: |
10.48350/151556 |
URI: |
https://boris.unibe.ch/id/eprint/151556 |
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