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

Area of Science:

• Cellular biology
• Biochemistry
• Molecular mechanisms of protein degradation

Background:

• Cellular homeostasis relies on removing damaged proteins to prevent toxic buildup.
• Protein damage accumulates during aging, neurodegeneration, and stress, but triggers for selective removal are unclear.

Purpose of the Study:

• To identify specific protein modifications that induce degradation.
• To elucidate the molecular mechanism by which damaged proteins are recognized and cleared.

Main Methods:

• Semi-synthetic chemical biology approach coupled with cellular assays.
• CRISPR screening to identify protein "readers" of specific modifications.
• Ubiquitin ligase complex analysis and proteasomal degradation assays.

Main Results:

• C-terminal amide-bearing proteins (CTAPs) are rapidly cleared from human cells.
• FBXO31 was identified as a specific reader of C-terminal amides.
• SCF-FBXO31 ubiquitin ligase targets CTAPs for proteasomal degradation, particularly after oxidative stress.
• A neurodevelopmental disorder mutation disrupts CTAP recognition, causing toxicity.

Conclusions:

• CTAPs represent a novel class of protein degrons mediating selective protein clearance.
• The FBXO31-mediated pathway provides broad surveillance of chemically damaged proteins.
• Dysregulation of this pathway is implicated in neurodevelopmental disorders.