In their recent study, “Control of protein stability by posttranslational modifications“, Ji Min Lee, Henrik M. Hammarén, Mikhail M. Savitski, and Sung Hee Baek explore the role of post-translational modifications (PTMs) in regulating protein stability.
Proteins, the molecular engines of our cells, display vast functional and structural diversity. Though the primary sequences of these proteins are gene-encoded, the complexity expands exponentially via alternative splicing and PTMs, creating tens of millions of different “proteoforms”. PTMs are specific chemical alterations to proteins, with over 300 types identified, including phosphorylation, acetylation, methylation, and more.
One critical function influenced by PTMs is a protein’s stability. The primary PTM controlling protein stability is ubiquitination, a process that marks proteins for degradation through the ubiquitin-proteasomal system (UPS). This mechanism plays a significant role in various cellular pathways, including cell growth, differentiation, and proliferation. Notably, ubiquitination doesn’t directly regulate, but instead, follows other PTMs, providing an additional layer of control and fine-tuning before a protein is committed for degradation.
The researchers have identified areas on proteins called degrons, regulated by PTMs, that control protein stability. Some PTMs can activate degrons to expedite degradation, while others inactivate degrons, stabilizing the protein. Proteomic assessments have found that proteins carrying both ubiquitination and phosphorylation constitute prime candidates for regulatory roles linked to ubiquitination.
Their study further focuses on the burgeoning field of protein stability control by methylation, highlighting various molecular mechanisms that translate PTM-regulation into changes in protein stability. These mechanisms range from simple PTM-activated degrons to changes in a protein’s oligomericity or subcellular localization, all leading to altered protein degradation.
It’s crucial to understand that PTM-controlled protein stability plays a vital role in maintaining homeostasis and preventing disease. Aberrant changes in protein turnover can lead to diseases by impacting cell survival and proliferation. Therefore, understanding the dynamics and significance of PTMs in diseases could potentially enable effective intervention, prevention, and therapy development.
Their research, though primarily focused on UPS-mediated protein degradation or stabilization, does not ignore PTMs’ roles in regulating protein stability through lysosomal and non-proteasomal degradation pathways.
They also emphasize the diversity of PTMs and how they function sequentially or in concert to manage signalling pathways in human diseases. By reversibly altering a protein’s physicochemical properties, PTMs can change its conformation, function, and/or interaction interfaces. This, in turn, regulates protein stability, a process often bridging the gap between an E3 ligase and its substrates.
The study concludes by acknowledging the challenges ahead, including the identification of writer and eraser enzymes, physiological and pathological functions of different PTMs, and the specificity of E3 ubiquitin ligase. Nonetheless, it presents a hopeful future for the field, aided by novel proteomic techniques that could significantly expedite the identification and elucidation of PTM-controlled protein stability modules. This could lead not only to new drug targets but also a better understanding of the fundamental mechanisms underlying protein regulation.
Lee, J.M., Hammarén, H.M., Savitski, M.M. et al. Control of protein stability by post-translational modifications. Nat Commun 14, 201 (2023). https://doi.org/10.1038/s41467-023-35795-8