Recent research has identified C-terminal amides as novel degrons that significantly enhance protein degradation, with studies using semi-synthetic fluorescent reporters to measure protein stability in human cells.

The study also identified 427 cleavage sites associated with oxidative stress, revealing that cellular protein fragments can form due to oxidative damage.

A pathogenic mutation in FBXO31, specifically D334N, alters its ability to recognize substrates, potentially leading to the degradation of new targets and contributing to neurodevelopmental disorders.

A genome-wide CRISPR screen has established FBXO31 as a vital component of the SCF ubiquitin ligase complex, which is responsible for clearing C-terminal amidated proteins.

Proteins undergo a variety of modifications, including non-enzymatic changes due to oxidative damage, resulting in over 700 known modifications that complicate our understanding of protein homeostasis.

FBXO31 plays a critical role in responding to oxidative stress by targeting various proteins for degradation, thus acting as a quality control factor under stress conditions.

The significance of FBXO31 is underscored by its impact on protein quality control and cellular responses to oxidative stress, which can influence protein homeostasis and the development of diseases.

In the human body, over 600 ubiquitin ligases, including FBXO31, recognize specific interaction motifs known as degrons on target proteins to facilitate their degradation.

FBXO31 specifically binds to C-terminal amides with high affinity, selectively ubiquitylating amidated substrates while disregarding non-amidated forms.

The initiation of protein degradation is marked by post-translational modifications, particularly Lys48-linked poly-ubiquitylation, which signals proteins for proteolysis.

Maintaining cellular protein homeostasis involves regulating the production, location, and degradation of proteins, with the ubiquitin-proteasome system being essential for selective protein degradation.

FBXO31's ability to bind and ubiquitylate amidated proteins was confirmed through in vitro assays and co-immunoprecipitation experiments, reinforcing its role as a reader of C-terminal amides.

Experiments conducted in K562 and HEK293T cells demonstrated that the presence of a C-terminal amide is sufficient to trigger degradation across various protein and cellular contexts.