Structural and evolutionary insights into the eukaryotic RNase MRP ribonucleoprotein complex

Abstract

Abstract RNase MRP is a conserved eukaryotic ribonucleoprotein essential for precursor-rRNA processing and ribosome assembly. Despite previous studies of yeast RNase MRP, the composition of RNase MRP and how it adapts to process flexible, single-stranded rRNA substrates in most eukaryotes remain enigmatic. Here, we perform an integrative structural, evolutionary, and functional dissection of human RNase MRP. Using structure-based bioinformatics and cryo-EM structural analyses, we identify NEPRO (RMP64) and C18orf21 (RMP24) as the bona fide subunits unique to RNase MRP, which are indispensable for precursor-rRNA cleavage, ribosome assembly, protein synthesis, and chondrogenesis. The structure of human RNase MRP reveals a unique ‘double-anchor’ substrate-binding mechanism that underlies evolutionary adaptations conferring broad substrate specificity. Our work on RNase MRP provides a unified evolutionary and mechanistic framework for this essential ancient ribozyme.