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Crystal structure of the V(D)J recombinase RAG1–RAG2

Journal Article · · Nature (London)
DOI:https://doi.org/10.1038/nature14174· OSTI ID:1247328
 [1];  [2];  [1];  [1]
  1. National Inst. of Health (NIH), Bethesda, MD (United States)
  2. Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); National Inst. of Health (NIH), Bethesda, MD (United States)
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V(D)J recombination in the vertebrate immune system generates a highly diverse population of immunoglobulins and T-cell receptors by combinatorial joining of segments of coding DNA. The RAG1–RAG2 protein complex initiates this site-specific recombination by cutting DNA at specific sites flanking the coding segments. Here we report the crystal structure of the mouse RAG1–RAG2 complex at 3.2 Å resolution. The 230-kilodalton RAG1–RAG2 heterotetramer is ‘Y-shaped’, with the amino-terminal domains of the two RAG1 chains forming an intertwined stalk. Each RAG1–RAG2 heterodimer composes one arm of the ‘Y’, with the active site in the middle and RAG2 at its tip. The RAG1–RAG2 structure rationalizes more than 60 mutations identified in immunodeficient patients, as well as a large body of genetic and biochemical data. Here, the architectural similarity between RAG1 and the hairpin-forming transposases Hermes and Tn5 suggests the evolutionary conservation of these DNA rearrangements.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of Health
OSTI ID:
1247328
Journal Information:
Nature (London), Journal Name: Nature (London) Journal Issue: 7540 Vol. 518; ISSN 0028-0836
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (39)

DNA recombination defects in Kuwait: Clinical, immunologic and genetic profile journal February 2018
Transposons to V(D)J Recombination: Evolution of the RAG Reaction journal August 2019
HIV integrase inhibitor, Elvitegravir, impairs RAG functions and inhibits V(D)J recombination journal June 2017
DNA melting initiates the RAG catalytic pathway journal July 2018
The R229Q mutation of Rag2 does not characterize severe immunodeficiency in mice journal March 2019
The evolution of zebrafish RAG2 protein is required for adapting to the elevated body temperature of the higher endothermic vertebrates journal March 2020
Biochemical Characterization of Nonamer Binding Domain of RAG1 Reveals its Thymine Preference with Respect to Length and Position journal January 2016
The murine IgH locus contains a distinct DNA sequence motif for the chromatin regulatory factor CTCF journal July 2019
Orientation-specific RAG activity in chromosomal loop domains contributes to Tcrd V(D)J recombination during T cell development journal August 2016
Correction: RAG1/2 induces genomic insertions by mobilizing DNA into RAG1/2-independent breaks journal June 2017
Mu transpososome activity-profiling yields hyperactive MuA variants for highly efficient genetic and genome engineering journal December 2017
Transposition of Mutator–like transposable elements (MULEs) resembles hAT and Transib elements and V(D)J recombination journal May 2017
Structural insights into the mechanism of double strand break formation by Hermes, a hAT family eukaryotic DNA transposase journal September 2018
Using bioinformatic and phylogenetic approaches to classify transposable elements and understand their complex evolutionary histories journal December 2017
Rapid generation of novel models of RAG1 deficiency by CRISPR/Cas9-induced mutagenesis in murine zygotes journal February 2016
HIV‑1 integrase inhibitors targeting various DDE transposases: Retroviral integration versus RAG‑mediated recombination (Review) journal October 2019
Additional file 1 of A variant of RAG1 gene identified in severe combined immunodeficiency: a case report dataset January 2023
The RAG transposon is active through the deuterostome evolution and domesticated in jawed vertebrates journal April 2017
RAG Deficiency: Two Genes, Many Diseases journal July 2018
Human RAG mutations: biochemistry and clinical implications journal March 2016
Genome organization in immune cells: unique challenges journal March 2019
Transposon molecular domestication and the evolution of the RAG recombinase journal April 2019
The fundamental role of chromatin loop extrusion in physiological V(D)J recombination journal September 2019
Structures of a RAG-like transposase during cut-and-paste transposition journal November 2019
Cation trafficking propels RNA hydrolysis journal August 2018
Structure of a P element transposase–DNA complex reveals unusual DNA structures and GTP-DNA contacts journal October 2019
Structure of the P element transpososome reveals new twists on the DD(E/D) theme journal October 2019
Cutting antiparallel DNA strands in a single active site journal February 2020
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DJ Pairing during VDJ Recombination Shows Positional Biases That Vary among Individuals with Differing IGHD Locus Immunogenotypes journal December 2015

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