Ribosomal protein with conserved function has entirely different structures in different organisms

It is generally accepted that protein structures are more conserved than protein sequences. This notion is widely used to identify distant protein homologs and predict the structure and functions of uncharacterized proteins. However, this principle has been derived from studies of globular proteins, leaving it unclear whether the same principle is applied to non-globular (or intrinsically disordered) proteins. Here, to help answer this question, we describe the evolution of the ribosomal protein msL1/msL2 that was recently found in ribosomes from the parasitic microorganisms microsporidia. We first show that this protein has conserved function but entirely dissimilar structures in different organisms: in each of the analyzed species, msL1/msL2 exhibits an altered secondary structure, an inverted orientation of the N- and C-termini, and a completely transformed fold. We then show that this fold change is likely caused by the evolution of the msL1/msL2-binding site in the ribosome; specifically, by variations in microsporidian rRNA. These findings illustrate that structure may evolve faster than sequence in non-globular proteins. Hence, non-globular proteins can completely transform their fold without loss of function, challenging the current sequence-structure-function paradigm that is viewed as a universal principle of protein evolution. ### Competing Interest Statement The authors have declared no competing interest.