Emergence and evolution of an interaction between intrinsically disordered proteins

TLDR: Experiments together with molecular modeling using NMR chemical shifts suggest that new interactions involving intrinsically disordered proteins may evolve via a low-affinity complex which is optimized by modulating direct interactions as well as dynamics, while tolerating several potentially disruptive mutations.

Abstract: Proteins are an important building block of life and are vital for almost every process that keeps cells alive. These molecules are made from chains of smaller molecules called amino acids linked together. The specific order of amino acids in a protein determines its shape and structure, which in turn controls what the protein can do. However, a group of proteins called 'intrinsically disordered proteins' are flexible in their shape and lack a stable three-dimensional structure. Yet, these proteins play important roles in many processes that require the protein to interact with a number of other proteins. At multiple time points during evolution, new or modified proteins – and consequently new potential interactions between proteins – have emerged. Often, an interaction that is specific for a group of organisms has evolved a long time ago and not changed since. As intrinsically disordered proteins lack a specific shape, it is harder to study how their structure (or lack of it) influences their purpose; until now, it was not known how their interactions emerge and evolve. Hultqvist et al. analyzed the amino acid sequences of two specific intrinsically disordered proteins from different organisms to reconstruct the versions of the proteins that were likely found in their common ancestors 450-600 million years ago. The ancestral proteins were then ‘resurrected’ by recreating them in test tubes and their characteristics and properties analyzed with experimental and computational biophysical methods. The results showed that the ancestral proteins created weaker bonds between them compared to more ‘modern’ ones, and were more flexible even when bound together. However, once their connection had evolved, the bonds became stronger and were maintained even when the organism diversified into new species. The findings shed light on fundamental principles of how new protein-protein interactions emerge and evolve on a molecular level. This suggests that an originally weak and dynamic interaction is relatively quickly turned into a tighter one by random mutations and natural selection. A next step for the future will be to investigate how other protein-protein interactions have evolved and to identify general underlying patterns. A deeper knowledge of how this molecular evolution happened will broaden our understanding of present day protein-protein interactions and might aid the design of drugs that can mimick proteins.