Recombination activating gene

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The recombination activating genes encode enzymes that play an important role in the rearrangement and recombination of the genes of immunoglobulin and T cell receptor molecules during the process of VDJ recombination. There are two recombination activating gene products known as RAG-1 and RAG-2, whose cellular expression is restricted to lymphocytes during their developmental stages. RAG-1 and RAG-2 are essential to the generation of mature B and T lymphocytes, two cell types that are crucial components of the adaptive immune system.

[edit] Function of RAG proteins

RAG enzymes work as a multi-subunit complex to induce cleavage of a single double stranded DNA (dsDNA) molecule between the antigen receptor coding segment and a flanking recombination signal sequence (RSS). They do this in two steps. They initially introduce a ‘nick’ in the 5' (upstream) end of the RSS heptamer (a conserved region of 7 nucleotides) that is adjacent to the coding sequence, leaving behind a specific biochemical structure on this region of DNA; a 3'-hydroxyl (OH) group at the coding end and a 5'-phosphate (PO4) group at the RSS end. The next step couples these chemical groups, binding the OH-group (on the coding end) to the PO4-group (that is sitting between the RSS and the gene segment on the opposite strand). This produces a 5'-phosphorylated double-stranded break at the RSS and a covalently closed hairpin at the coding end. The RAG proteins remain at these junctions until other enzymes repair the DNA breaks.

RAG proteins are important in rearrangement of genetic components during B and T cell maturation, as well as the phenomena of class-switching and affinity maturation in activated B cells.

[edit] Structure of RAG proteins

As with many enzymes, RAG proteins are fairly large. For example, mouse RAG-1 contains 1040 amino acids and mouse RAG-2 contains 527 amino acids. The enzymatic activity of the RAG proteins is largely concentrated in a core region; residues 384–1008 of RAG-1 and residues 1–387 of RAG-2 retain most of the DNA cleavage activity. The RAG-1 core contains three acidic residues (D600, D708, and E962) in what is called the DDE motif, the major active site for DNA cleavage. These residues are critical for nicking the DNA strand and for forming the DNA hairpin. Residues 384–454 of RAG-1 comprise a nonamer-binding region (NBR) that specifically binds the conserved nonomer (9 nucleotides) of the RSS and the central domain (amino acids 528–760) of RAG-1 binds specifically to the RSS heptamer. The core region of RAG-2 is predicted to form a six-bladed beta-propeller structure that appears less specific than RAG-1 for its target.

[edit] References

  1. Janeway CA, Jr. et al (2005). Immunobiology., 6th ed., Garland Science. ISBN 0443073104.
  2. Abbas AK and Lichtman AH (2003). Cellular and Molecular Immunology, 5th ed., Saunders, Philadelphia. ISBN 0-7216-0008-5.
  3. Sadofsky MJ (2004). "Recombination-activating gene proteins: more regulation, please.". Immunological Reviews 200: 83-89. PMID: 15242398.
  4. De P and Rodgers KK (2004). "Putting the pieces together: identification and characterization of structural domains in the V(D)J recombination protein RAG1.". Immunological Reviews 200: 70-82. PMID: 15242397.
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