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Recombination activating gene



recombination activating gene 1
Identifiers
Symbol RAG1
Entrez 5896
HUGO 9831
OMIM 179615
RefSeq NM_000448
UniProt P15918
Other data
Locus Chr. 11 p13
recombination activating gene 2
Identifiers
Symbol RAG2
Entrez 5897
HUGO 9832
OMIM 179616
RefSeq NM_000536
UniProt P55895
Other data
Locus Chr. 11 p13

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.

Contents

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.

The RAG proteins initiate V(D)J recombination, which is essential for the maturation of pre-B and pre-T cells. Activated mature B cells also possess two other remarkable, RAG independent, phenomena of manipulating their own DNA; so-called class-switch recombination (AKA isotype switching) and somatic hypermutation (AKA affinity maturation).

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.

See also

References

  • Janeway CA, Jr. et al (2005). Immunobiology., 6th ed., Garland Science. ISBN 0-443-07310-4. 
  • Abbas AK and Lichtman AH (2003). Cellular and Molecular Immunology, 5th ed., Saunders, Philadelphia. ISBN 0-7216-0008-5. 
  • Sadofsky M. "Recombination-activating gene proteins: more regulation, please". Immunol Rev 200: 83-9. PMID 15242398.
  • De P, Rodgers K. "Putting the pieces together: identification and characterization of structural domains in the V(D)J recombination protein RAG1". Immunol Rev 200: 70-82. PMID 15242397.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Recombination_activating_gene". A list of authors is available in Wikipedia.
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