2. Academic Validation
  3. C-terminal amides mark proteins for degradation via SCF-FBXO31

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

  • Nature. 2025 Jan 29. doi: 10.1038/s41586-024-08475-w.
Matthias F Muhar # 1,  Jakob Farnung # 2 3,  Martina Cernakova 1,  Raphael Hofmann 2,  Lukas T Henneberg 3,  Moritz M Pfleiderer 4,  Annina Denoth-Lippuner 5,  Filip Kalčic 2,  Ajse S Nievergelt 4,  Marwa Peters Al-Bayati 1,  Nikolaos D Sidiropoulos 1,  Viola Beier 3,  Matthias Mann 6,  Sebastian Jessberger 5,  Martin Jinek 4,  Brenda A Schulman 3,  Jeffrey W Bode 7,  Jacob E Corn 8
Affiliations

Affiliations

  • 1 Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
  • 2 Laboratory for Organic Chemistry, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
  • 3 Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 4 Department of Biochemistry, University of Zurich, Zurich, Switzerland.
  • 5 Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich, Switzerland.
  • 6 Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 7 Laboratory for Organic Chemistry, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland. bode@org.chem.ethz.ch.
  • 8 Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland. jacob.corn@biol.ethz.ch.
  • # Contributed equally.
PMID: 39880951 DOI: 10.1038/s41586-024-08475-w
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.

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