MPI-NAT Seminar: How chemical scars mark proteins for degradation
MPI-NAT Seminar
- Date: Apr 16, 2025
- Time: 11:00 AM - 12:00 PM (Local Time Germany)
- Speaker: Matthias Muhar
- ETH Zürich
- Location: Max-Planck-Institut für Multidisziplinäre Naturwissenschaften (MPI-NAT, Faßberg-Campus)
- Room: Large Seminar Room
- Host: Christian Griesinger & Sonja Lorenz
- Contact: elisa.reckmann@mpinat.mpg.de
Human cells have the remarkable ability to identify and remove individual damaged proteins among a sea of intact ones. But how do cells surveil the highly diverse human proteome for damaged, excess or mislocalized proteins?
In recent work, I discovered that human cells scan protein C-termini for a minimal chemical modification that marks damaged proteins following oxidative fragmentation (Muhar, Farnung et al. 2025, Nature). By precisely modelling protein damage using chemical biology tools, I identified that cells selectively degrade C-terminal amide-bearing proteins (CTAPs). A genome-wide CRISPR screen identified SCF/FBXO31 as the reader of C-terminal amidation which directly recognizes and ubiquitylates CTAPs. SCF/FBXO31 binds diverse C-terminal sequences with high affinity, yet exquisite selectivity over unmodified ones. A mutation found in cerebral palsy patients shifts client selection towards unmodified C-termini, thereby forming a toxic ubiquitin ligase.
This work demonstrates how a chemical mark enables broad yet selective proteome surveillance, which could represent a common strategy by which cells maintain protein homeostasis. In my future work, I will explore how recognition of CTAPs and similar modifications shapes the human proteome. I will dissect how cells toggle global proteome turnover during developmental transitions and how different cell types tailor the proteome to their specialized functions.
In recent work, I discovered that human cells scan protein C-termini for a minimal chemical modification that marks damaged proteins following oxidative fragmentation (Muhar, Farnung et al. 2025, Nature). By precisely modelling protein damage using chemical biology tools, I identified that cells selectively degrade C-terminal amide-bearing proteins (CTAPs). A genome-wide CRISPR screen identified SCF/FBXO31 as the reader of C-terminal amidation which directly recognizes and ubiquitylates CTAPs. SCF/FBXO31 binds diverse C-terminal sequences with high affinity, yet exquisite selectivity over unmodified ones. A mutation found in cerebral palsy patients shifts client selection towards unmodified C-termini, thereby forming a toxic ubiquitin ligase.
This work demonstrates how a chemical mark enables broad yet selective proteome surveillance, which could represent a common strategy by which cells maintain protein homeostasis. In my future work, I will explore how recognition of CTAPs and similar modifications shapes the human proteome. I will dissect how cells toggle global proteome turnover during developmental transitions and how different cell types tailor the proteome to their specialized functions.