Dissecting the immune response

2015

Challenge

The RAG1 and RAG2 proteins work together to initiate the complex cut-and-paste process of coding DNA that allows the immune system to fight off a large variety of infections. Mutations of these proteins are known to cause a sizable fraction of immune deficiencies in children, but the complex interaction of the RAG proteins was not well understood.

Advance

IRP researchers led by Wei Yang, Ph.D., and Martin Gellert, Ph.D., captured a detailed three-dimensional crystal structure of the RAG1-RAG2 protein complex, allowing them to characterize more than 60 mutations known to result in immunodeficiency. The close relationship of the RAG1-RAG2 complex to other species’ DNA rearranging proteins demonstrates that these proteins have been highly conserved. 

Impact

Visualizing the RAG1-RAG2 structure not only helps to explain the functional defects of known disease mutations, but can now help researchers understand the many immunodeficiencies that do not yet have a known underlying mutation.

Publications

Min-Sung Kim, Mikalai Lapkouski, Wei Yang, & Martin Gellert. (2015). Crystal structure of the V(D)J recombinase RAG1–RAG2. Nature 518, 507.