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The RAG complex protein is composed of two subunits, RAG-1 and RAG-2. RAG-1 and RAG-2 are critical in T and B cell maturation, promoting an adaptive immune response.

Function

This RAG complex protein allows the human body to have diverse immune response. Using both RAG-1 and RAG-2 together allows for recombination to occur to create cell receptors on both B and T cells. It is critical that the cell receptors are diverse in order to recognize a wide variety of pathogens and protect the body. RAG-1 and RAG-2 appear in the body as a complex. Both RAG-1 and RAG-2 are necessary for the function of the protein. RAG-1 cannot perform all of the functions by itself associated with the RAG protein; similarly, RAG-2 cannot perform all of the functions alone. The RAG-1 protein will bind to a specific recombination signal sequence within the V-J region of the light chain and the D-J segment along with the V-DJ segment of a heavy chain ^[1]. Next, RAG-1 will bring the various segments within close proximity, looping the DNA between the segments out. RAG-2 will then cut the RSS sequence and a different protein will bind the two DNA ends ^[2].

Disease

Mutated RAG-1 or RAG-2 prevents a fully functional immune system from developing. Defects in RAG1 or RAG2 cause impaired V(D)J recombination and this leads to defective expression of the pre-TCR and pre-BCR, a critical event in the development of T cells and B cells. In classical experiments, null mutations of the RAG 1 and RAG 2 allele cause severe immunodeficiency disease (SCID), wherein B and T cell development does not occur. In vivo experiments with RAG1 or RAG2 deficiency reveal that the complex can be partially mutated. In this case, the semi-functional RAG complex is linked to Omenn Syndrome. Omenn Syndrome is associated with severe immunodeficiency ^[3].

Relevance

This protein is predominantly important during the B and T cell development. Because humans need to be well-protected from antigens, B cells and T cells must have a variety of proteins on their surface in order to recognize a variety of invaders. Causing these proteins to become diverse involves a series of segments known as Variable (V), Diversity (D), and Joining (J) segments ^[4]. These segments can be arranged in many combinations of sequences that ensure variable surface proteins. Without the RAG protein, B and T cells would lack the ability to identify and destroy foreign pathogens ^[5]

Structural highlights

found in RAG complex.

is the dimerization formation of RAG-1. It features four zinc binding-motifs that assist in RAG1 binding to the specific recombination signal sequence.

is the asymmetrical crystal structure of RAG1, featuring the dimer bound to a DNA molecule. In reality, the dimer binds two DNA molecules, one bound in a cis configuration and the other bound in trans configuration.

contains a plant homeodomain (PHD) near its C terminus (RAG2-PHD). This is unique because when a peptide is not being modified, a peptide N-terminal occupies the binding site, meaning that it is self-regulated. There is significantly less structural data on RAG2 due to a debate about the function of RAG2. Many challenge the belief that RAG2 cuts the RSS sequence, believing instead that RAG2 acts as a regulatory component to the complex.