How structural disorder and polyelectrolyte properties of prothymosin α enable its large interactome

Prothymosin α (ProTα) is a conserved, highly negatively charged multifunctional and multivalent protein of higher eukaryotes. It engages in diverse protein complexes where it exhibits different binding modes. These range from binding via short linear motifs to remaining fully disordered and highly dynamic in complexes with either disordered or folded proteins. In this review, we highlight how the physicochemical properties of ProTα enable high-affinity dynamic complexes, competitive substitution through the formation of ternary complexes, complex coacervation and multispecificity. We highlight functions of ProTα both inside and outside the nucleus, including those in the extracellular space, and describe how cellular stresses reallocate the functions of ProTα to make it act as an alarmin and modulator of the immune response. While most binding partners of ProTα are highly positively charged, matching the negative charge of ProTα, others are not, and the molecular details of many interactions with ProTα are still lacking, impacting how we understand specificity in interactions involving biological polyelectrolytes.