Recombination-activating gene
Recombination Activating Gene Complex
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. FunctionThis 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. Gene recombination, known as Variable, Diverse, and Joining (V(D)J) recombination, is only found in developing B and T cells. V(D)J recombination results in unique amino acid sequences. It is critical that the cell receptors are diverse in order to recognize a wide variety of pathogens and protect the body. Within the human body, the developing antibodies, each composed of heavy and light chains. Within the heavy chain, DJ recombination occurs first, and then V and DJ recombination occurs. The light chain, however, only has VJ recombination. The newly formed interactions between each gene segment gives rise to a unique heavy and unique light chain. The interaction between heavy and light chains form the classic antibody structure, promoting the function. The process of V(D)J recombination cannot occur without the help of the RAG complex [1]. RAG-1 and RAG-2 appear in the body as one 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 [2]. 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 [3].
DiseaseMutated 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 [4]. RelevanceThis 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 [5]. 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 [6] Structural highlightsNucleic Acids found in RAG complex. This is the dimerization formation of RAG-1. It features four zinc binding-motifs that assist in RAG1 binding to the specific recombination signal sequence. This 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. RAG2 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.
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