2022/11/09 by Estella A. Newcombe, Estella A. Newcombe, Elise Delaforge +5 · 113 citations
Biochemistry, Genetics and Molecular Biology · Chemistry · Neuroscience · #Biochemistry #Biology #Biophysics #Cell biology #Chemistry #Circadian rhythm and melatonin #Computational biology #Endoplasmic Reticulum Stress and Disease #Function (biology) #Intrinsically disordered proteins #Phosphorylation #Protein Structure and Dynamics
paper · pdf · doi:10.1042/ebc20220060
published in Essays in Biochemistry 66(7), 901-913 (Portland Press)
openalex publication_date 2022/11/09 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/04
Phosphorylation is the most common post-translational modification (PTM) in eukaryotes, occurring particularly frequently in intrinsically disordered proteins (IDPs). These proteins are highly flexible and dynamic by nature. Thus, it is intriguing that the addition of a single phosphoryl group to a disordered chain can impact its function so dramatically. Furthermore, as many IDPs carry multiple phosphorylation sites, the number of possible states increases, enabling larger complexities and novel mechanisms. Although a chemically simple and well-understood process, the impact of phosphorylation on the conformational ensemble and molecular function of IDPs, not to mention biological output, is highly complex and diverse. Since the discovery of the first phosphorylation site in proteins 75 years ago, we have come to a much better understanding of how this PTM works, but with the diversity of IDPs and their capacity for carrying multiple phosphoryl groups, the complexity grows. In this Essay, we highlight some of the basic effects of IDP phosphorylation, allowing it to serve as starting point when embarking on studies into this topic. We further describe how recent complex cases of multisite phosphorylation of IDPs have been instrumental in widening our view on the effect of protein phosphorylation. Finally, we put forward perspectives on the phosphorylation of IDPs, both in relation to disease and in context of other PTMs; areas where deep insight remains to be uncovered.