Recombination-activating gene
Chr. 11 p13 | |||||||
---|---|---|---|---|---|---|---|
|
Chr. 11 p13 | |||||||
---|---|---|---|---|---|---|---|
|
Recombination-activating protein 2 | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
Symbol | RAG2 | ||||||||
Pfam | PF03089 | ||||||||
InterPro | IPR004321 | ||||||||
|
Recombination-activating protein 1 | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
Symbol | RAG1 | ||||||||
Pfam | PF12940 | ||||||||
InterPro | IPR004321 | ||||||||
|
The recombination-activating genes (RAGs) encode parts of a
Function
In the vertebrate immune system, each antibody is customized to attack one particular antigen (foreign proteins and carbohydrates) without attacking the body itself. The human genome has at most 30,000 genes, and yet it generates millions of different antibodies, which allows it to be able to respond to invasion from millions of different antigens. The immune system generates this diversity of antibodies by shuffling, cutting and recombining a few hundred genes (the VDJ genes) to create millions of permutations, in a process called V(D)J recombination.[1] RAG-1 and RAG-2 are proteins at the ends of VDJ genes that separate, shuffle, and rejoin the VDJ genes. This shuffling takes place inside B cells and T cells during their maturation.
RAG enzymes work as a multi-subunit complex to induce cleavage of a single double stranded
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).[2] Current studies have indicated that RAG-1 and RAG-2 must work in a synergistic manner to activate VDJ recombination. RAG-1 was shown to inefficiently induce recombination activity of the VDJ genes when isolated and transfected into fibroblast samples. When RAG-1 was cotransfected with RAG-2, recombination frequency increased by a 1000-fold.[3] This finding has fostered the newly revised theory that RAG genes may not only assist in VDJ recombination, but rather, directly induce the recombinations of the VDJ genes.
Structure
As with many enzymes, RAG proteins are fairly large. For example, mouse RAG-1 contains 1040
Evolution
This section is missing information about Specifics in 30971819.(May 2019) |
Based on core sequence homology, it is believed that RAG1 evolved from a
A transposon with RAG2 arranged next to RAG1 has been identified in the purple sea urchin.[8] Active Transib transposons with both RAG1 and RAG2 ("ProtoRAG") has been discovered in B. belcheri (Chinese lancelet) and Psectrotarsia flava (a moth).[9][10] The terminal inverted repeats (TIR) in lancelet ProtoRAG have a heptamer-spacer-nonamer structure similar to that of RSS, but the moth ProtoRAG lacks a nonamer. The nonamer-binding regions and the nonamer sequences of lancelet ProtoRAG and animal RAG are different enough to not recognize each other.[9] The structure of the lancelet protoRAG has been solved (PDB: 6b40), providing some understanding on what changes lead to the domestication of RAG genes.[11]
Although the transposon origins of these genes are well-established, there is still no consensus on when the ancestral RAG1/2 locus became present in the vertebrate genome. Because
Selective pressure
It is still unclear what forces led to the development of a RAG1/2-mediated immune system exclusively in jawed vertebrates and not in any invertebrate species that also acquired the RAG1/2-containing transposon. Current hypotheses include two whole-genome duplication events in vertebrates,[17] which would provide the genetic raw material for the development of the adaptive immune system, and the development of endothelial tissue, greater metabolic activity, and a decreased blood volume-to-body weight ratio, all of which are more specialized in vertebrates than invertebrates and facilitate adaptive immune responses.[18]
See also
References
Further reading
- Sadofsky MJ (Aug 2004). "Recombination-activating gene proteins: more regulation, please". Immunological Reviews. 200: 83–9. S2CID 23905210.
- De P, Rodgers KK (Aug 2004). "Putting the pieces together: identification and characterization of structural domains in the V(D)J recombination protein RAG1". Immunological Reviews. 200: 70–82. S2CID 22044642.
- Kapitonov VV, Jurka J (Jun 2005). "RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons". PLOS Biology. 3 (6): e181. PMID 15898832.
External links
- Travis J (November 1998). "The Accidental Immune System; Long ago, a wandering piece of DNA—perhaps from a microbe—created a key strategy" (PDF). Science News. 154 (19): 302–303. JSTOR 4010948. A simple explanation of recombination activating gene for the general reader.