Riches in RAGs: Revealing the V(D)J Recombinase through High-Resolution Structures

Development of the adaptive immune system is dependent on V(D)J recombination, which forms functional antigen receptor genes through rearrangement of component gene segments. The V(D)J recombinase, consisting of recombination-activating proteins RAG1 and RAG2, guides the initial DNA cleavage events to the recombination signal sequence (RSS), which flanks each gene segment. Although the enzymatic steps for RAG-mediated endonucleolytic activity was established over two decades ago, only recently have high resolution structural studies of the catalytically active core regions of the RAG proteins shed light on conformational requirements for the reaction. While outstanding questions remain, we have a clearer picture for how RAG proteins function in generating the diverse repertoires of antigen receptors, the underlying foundation of the adaptive immune system.