Sandbox GGC9
From Proteopedia
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| - | ==Structure of RAG1/2-DNA Strand Transfer Complex (paired conformation)== | + | =='''Structure of RAG1/2-DNA Strand Transfer Complex (paired conformation)'''== |
<StructureSection load='6XNY' size='340' side='right' caption='Structure of RAG1/2-DNA Strand Transfer Complex (Paired Conformation)' scene='75/752271/Rag_complex_background/1'> | <StructureSection load='6XNY' size='340' side='right' caption='Structure of RAG1/2-DNA Strand Transfer Complex (Paired Conformation)' scene='75/752271/Rag_complex_background/1'> | ||
RAG1 is the catalytic component of the RAG Complex. Together with RAG2, the RAG Complex functions to create antibodies for virtually any antigen. | RAG1 is the catalytic component of the RAG Complex. Together with RAG2, the RAG Complex functions to create antibodies for virtually any antigen. | ||
| - | == Function == | + | == '''Function''' == |
RAG1 and RAG2 form the RAG Complex (RAG Recombinases), which is responsible for regulating the DNA cleavage phase during recombination. V(D)J recombination functions to produce a plethora of immune molecules in developing B and T-lymphocytes. The V stands for variable, D, diversity and J joining of the gene segments. RAG1 functions as the catalytic portion while RAG2, although not catalytic, is required for RAG1 to function.[1] RAG1 controls the ability of the DNA to bind to the RSS or recombination signal sequences. This is achieved by the ability of the RAG1 complex to create a double-stranded break between the (RSS) and the adjacent coding sequence. This process is executed in the following way: introduction of a nick, creating a 3'-hydroxyl group which attacks the phosphodiester bond on the opposite strand.[1] This is a direct transesterification reaction which results in four DNA ends. Histones also assist in the nicking and hairpinning of the strands. The result is the recombination of variable genes joining.[1] Additionally to the role played in V(D)J, RAG also assists in pre-B cell allelic exclusion. This means that there is a recombination of the second allele. RAG1 also possess ubiquitin properties. Newer Studies suggest that the RAG1/2 recombinase complex acts as a domesticated transposase.[2] | RAG1 and RAG2 form the RAG Complex (RAG Recombinases), which is responsible for regulating the DNA cleavage phase during recombination. V(D)J recombination functions to produce a plethora of immune molecules in developing B and T-lymphocytes. The V stands for variable, D, diversity and J joining of the gene segments. RAG1 functions as the catalytic portion while RAG2, although not catalytic, is required for RAG1 to function.[1] RAG1 controls the ability of the DNA to bind to the RSS or recombination signal sequences. This is achieved by the ability of the RAG1 complex to create a double-stranded break between the (RSS) and the adjacent coding sequence. This process is executed in the following way: introduction of a nick, creating a 3'-hydroxyl group which attacks the phosphodiester bond on the opposite strand.[1] This is a direct transesterification reaction which results in four DNA ends. Histones also assist in the nicking and hairpinning of the strands. The result is the recombination of variable genes joining.[1] Additionally to the role played in V(D)J, RAG also assists in pre-B cell allelic exclusion. This means that there is a recombination of the second allele. RAG1 also possess ubiquitin properties. Newer Studies suggest that the RAG1/2 recombinase complex acts as a domesticated transposase.[2] | ||
| - | == Disease == | + | == '''Disease''' == |
Mutations of the RAG recombinases are often occurring in patients being displaying immunodeficiency and Omenn syndrome. [3] Omenn's syndrome is a severe combined immunodeficiency. [4] Some characteristics include redness of skin, peeling skin, hair loss, chronic diarrhea, enlarged lymph nodes, swelling of liver and spleen, and increased levels of of serum IgE. [4] | Mutations of the RAG recombinases are often occurring in patients being displaying immunodeficiency and Omenn syndrome. [3] Omenn's syndrome is a severe combined immunodeficiency. [4] Some characteristics include redness of skin, peeling skin, hair loss, chronic diarrhea, enlarged lymph nodes, swelling of liver and spleen, and increased levels of of serum IgE. [4] | ||
| - | == Relevance == | + | == '''Relevance''' == |
Early intervention of people with Omenn's syndrome is important, because if left untreated it will be fatal. [4] Treatment of Omenn's syndrome includes bone marrow or cord blood stem cell transplantation. [4] | Early intervention of people with Omenn's syndrome is important, because if left untreated it will be fatal. [4] Treatment of Omenn's syndrome includes bone marrow or cord blood stem cell transplantation. [4] | ||
| - | == Structural highlights == | + | == '''Structural highlights''' == |
The subunit structure is defined as a homodimer. | The subunit structure is defined as a homodimer. | ||
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</StructureSection> | </StructureSection> | ||
| - | == References == | + | == '''References''' == |
<references/> | <references/> | ||
Revision as of 22:50, 22 April 2021
Structure of RAG1/2-DNA Strand Transfer Complex (paired conformation)
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References
[1] Grazini U, Zanardi F, Citterio E, Casola S, Goding CR, McBlane F. The RING domain of RAG1 ubiquitylates histone H3: a novel activity in chromatin-mediated regulation of V(D)J joining. Mol Cell. 2010 Jan 29;37(2):282-93. doi: 10.1016/j.molcel.2009.12.035. PMID: 20122409.
[2] Zhang Y, Corbett E, Wu S, Schatz DG. Structural basis for the activation and suppression of transposition during evolution of the RAG recombinase. EMBO J. 2020 Nov 2;39(21):e105857. doi: 10.15252/embj.2020105857. Epub 2020 Sep 18. PMID: 32945578; PMCID: PMC7604617.
[3] Chen, Karin et al. “Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations.” The Journal of allergy and clinical immunology vol. 133,3 (2014): 880-2.e10. doi:10.1016/j.jaci.2013.11.038
[4] Omenn syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. Rarediseases.info.nih.gov. (2021). Retrieved 7 April 2021, from https://rarediseases.info.nih.gov/diseases/8198/omenn-syndrome.
[5] Gwyn, Lori M et al. “A zinc site in the C-terminal domain of RAG1 is essential for DNA cleavage activity.” Journal of molecular biology vol. 390,5 (2009): 863-78. doi:10.1016/j.jmb.2009.05.076
