PUBLICATION
Molecular Mechanism of V(D)J Recombination from Synaptic RAG1-RAG2 Complex Structures
- Authors
- Ru, H., Chambers, M.G., Fu, T.M., Tong, A.B., Liao, M., Wu, H.
- ID
- ZDB-PUB-170214-82
- Date
- 2015
- Source
- Cell 163: 1138-52 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Cryoelectron Microscopy
- Homeodomain Proteins/chemistry*
- Homeodomain Proteins/genetics
- Homeodomain Proteins/ultrastructure
- Humans
- V(D)J Recombination*
- Mice
- Amino Acid Sequence
- Mutation
- DNA-Binding Proteins/chemistry*
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/ultrastructure
- Multiprotein Complexes/chemistry
- Multiprotein Complexes/ultrastructure
- Zebrafish
- Sequence Alignment
- Molecular Sequence Data
- PubMed
- 26548953 Full text @ Cell
Citation
Ru, H., Chambers, M.G., Fu, T.M., Tong, A.B., Liao, M., Wu, H. (2015) Molecular Mechanism of V(D)J Recombination from Synaptic RAG1-RAG2 Complex Structures. Cell. 163:1138-52.
Abstract
Diverse repertoires of antigen-receptor genes that result from combinatorial splicing of coding segments by V(D)J recombination are hallmarks of vertebrate immunity. The (RAG1-RAG2)2 recombinase (RAG) recognizes recombination signal sequences (RSSs) containing a heptamer, a spacer of 12 or 23 base pairs, and a nonamer (12-RSS or 23-RSS) and introduces precise breaks at RSS-coding segment junctions. RAG forms synaptic complexes only with one 12-RSS and one 23-RSS, a dogma known as the 12/23 rule that governs the recombination fidelity. We report cryo-electron microscopy structures of synaptic RAG complexes at up to 3.4 Å resolution, which reveal a closed conformation with base flipping and base-specific recognition of RSSs. Distortion at RSS-coding segment junctions and base flipping in coding segments uncover the two-metal-ion catalytic mechanism. Induced asymmetry involving tilting of the nonamer-binding domain dimer of RAG1 upon binding of HMGB1-bent 12-RSS or 23-RSS underlies the molecular mechanism for the 12/23 rule.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping