UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER

Paul A. DaRosa, Ivan Penchev, Samantha C. Gumbin, Francesco Scavone, Magda Wąchalska, Joao A. Paulo, Alban Ordureau, Joshua J. Peter, Yogesh Kulathu, J. Wade Harper, Thomas Becker, Roland Beckmann () and Ron R. Kopito ()
Additional contact information
Paul A. DaRosa: Stanford University
Ivan Penchev: University of Munich
Samantha C. Gumbin: Stanford University
Francesco Scavone: Stanford University
Magda Wąchalska: Stanford University
Joao A. Paulo: Harvard Medical School
Alban Ordureau: Harvard Medical School
Joshua J. Peter: University of Dundee
Yogesh Kulathu: University of Dundee
J. Wade Harper: Harvard Medical School
Thomas Becker: University of Munich
Roland Beckmann: University of Munich
Ron R. Kopito: Stanford University

Nature, 2024, vol. 627, issue 8003, 445-452

Abstract: Abstract Reversible modification of target proteins by ubiquitin and ubiquitin-like proteins (UBLs) is widely used by eukaryotic cells to control protein fate and cell behaviour1. UFM1 is a UBL that predominantly modifies a single lysine residue on a single ribosomal protein, uL24 (also called RPL26), on ribosomes at the cytoplasmic surface of the endoplasmic reticulum (ER)2,3. UFM1 conjugation (UFMylation) facilitates the rescue of 60S ribosomal subunits (60S) that are released after ribosome-associated quality-control-mediated splitting of ribosomes that stall during co-translational translocation of secretory proteins into the ER3,4. Neither the molecular mechanism by which the UFMylation machinery achieves such precise target selection nor how this ribosomal modification promotes 60S rescue is known. Here we show that ribosome UFMylation in vivo occurs on free 60S and we present sequential cryo-electron microscopy snapshots of the heterotrimeric UFM1 E3 ligase (E3(UFM1)) engaging its substrate uL24. E3(UFM1) binds the L1 stalk, empty transfer RNA-binding sites and the peptidyl transferase centre through carboxy-terminal domains of UFL1, which results in uL24 modification more than 150 Å away. After catalysing UFM1 transfer, E3(UFM1) remains stably bound to its product, UFMylated 60S, forming a C-shaped clamp that extends all the way around the 60S from the transfer RNA-binding sites to the polypeptide tunnel exit. Our structural and biochemical analyses suggest a role for E3(UFM1) in post-termination release and recycling of the large ribosomal subunit from the ER membrane.

Date: 2024
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DOI: 10.1038/s41586-024-07073-0

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