C-terminal amides mark proteins for degradation via SCF–FBXO31

Matthias F. Muhar, Jakob Farnung, Martina Cernakova, Raphael Hofmann, Lukas T. Henneberg, Moritz M. Pfleiderer, Annina Denoth-Lippuner, Filip Kalčic, Ajse S. Nievergelt, Marwa Peters Al-Bayati, Nikolaos D. Sidiropoulos, Viola Beier, Matthias Mann, Sebastian Jessberger, Martin Jinek, Brenda A. Schulman, Jeffrey W. Bode () and Jacob E. Corn ()
Additional contact information
Matthias F. Muhar: Swiss Federal Institute of Technology (ETH) Zurich
Jakob Farnung: Swiss Federal Institute of Technology (ETH) Zurich
Martina Cernakova: Swiss Federal Institute of Technology (ETH) Zurich
Raphael Hofmann: Swiss Federal Institute of Technology (ETH) Zurich
Lukas T. Henneberg: Max Planck Institute of Biochemistry
Moritz M. Pfleiderer: University of Zurich
Annina Denoth-Lippuner: University of Zurich
Filip Kalčic: Swiss Federal Institute of Technology (ETH) Zurich
Ajse S. Nievergelt: University of Zurich
Marwa Peters Al-Bayati: Swiss Federal Institute of Technology (ETH) Zurich
Nikolaos D. Sidiropoulos: Swiss Federal Institute of Technology (ETH) Zurich
Viola Beier: Max Planck Institute of Biochemistry
Matthias Mann: Max Planck Institute of Biochemistry
Sebastian Jessberger: University of Zurich
Martin Jinek: University of Zurich
Brenda A. Schulman: Max Planck Institute of Biochemistry
Jeffrey W. Bode: Swiss Federal Institute of Technology (ETH) Zurich
Jacob E. Corn: Swiss Federal Institute of Technology (ETH) Zurich

Nature, 2025, vol. 638, issue 8050, 519-527

Abstract: Abstract During normal cellular homeostasis, unfolded and mislocalized proteins are recognized and removed, preventing the build-up of toxic byproducts1. When protein homeostasis is perturbed during ageing, neurodegeneration or cellular stress, proteins can accumulate several forms of chemical damage through reactive metabolites2,3. Such modifications have been proposed to trigger the selective removal of chemically marked proteins3–6; however, identifying modifications that are sufficient to induce protein degradation has remained challenging. Here, using a semi-synthetic chemical biology approach coupled to cellular assays, we found that C-terminal amide-bearing proteins (CTAPs) are rapidly cleared from human cells. A CRISPR screen identified FBXO31 as a reader of C-terminal amides. FBXO31 is a substrate receptor for the SKP1–CUL1–F-box protein (SCF) ubiquitin ligase SCF–FBXO31, which ubiquitylates CTAPs for subsequent proteasomal degradation. A conserved binding pocket enables FBXO31 to bind to almost any C-terminal peptide bearing an amide while retaining exquisite selectivity over non-modified clients. This mechanism facilitates binding and turnover of endogenous CTAPs that are formed after oxidative stress. A dominant human mutation found in neurodevelopmental disorders reverses CTAP recognition, such that non-amidated neosubstrates are now degraded and FBXO31 becomes markedly toxic. We propose that CTAPs may represent the vanguard of a largely unexplored class of modified amino acid degrons that could provide a general strategy for selective yet broad surveillance of chemically damaged proteins.

Date: 2025
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DOI: 10.1038/s41586-024-08475-w

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