Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Nat Rev Immunol. 2022 Jun;22(6):353-370. doi: 10.1038/s41577-021-00628-6. Epub 2021 Oct 21.
Adaptive immunity in jawed vertebrates relies on the assembly of antigen receptor genes by the recombination activating gene 1 (RAG1)-RAG2 (collectively RAG) recombinase in a reaction known as V(D)J recombination. Extensive biochemical and structural evidence indicates that RAG and V(D)J recombination evolved from the components of a RAG-like (RAGL) transposable element through a process known as transposon molecular domestication. This Review describes recent advances in our understanding of the functional and structural transitions that occurred during RAG evolution. We use the structures of RAG and RAGL enzymes to trace the evolutionary adaptations that yielded a RAG recombinase with exquisitely regulated cleavage activity and a multilayered array of mechanisms to suppress transposition. We describe how changes in modes of DNA binding, alterations in the dynamics of protein-DNA complexes, single amino acid mutations and a modular design likely enabled RAG family enzymes to survive and spread in the genomes of eukaryotes. These advances highlight the insight that can be gained from viewing evolution of vertebrate immunity through the lens of comparative genome analyses coupled with structural biology and biochemistry.
有颌脊椎动物的适应性免疫依赖于重组激活基因 1 (RAG1)-RAG2（统称为 RAG）重组酶在 V(D)J 重组反应中对抗原受体基因进行组装。广泛的生化和结构证据表明，RAG 和 V(D)J 重组是通过称为转座子分子驯化的过程从 RAG 样（RAGL）转座元件的组成部分进化而来的。这篇综述描述了我们对 RAG 进化过程中发生的功能和结构转变的理解的最新进展。我们使用 RAG 和 RAGL 酶的结构来追踪进化适应，这些适应产生了具有高度调节性切割活性的 RAG 重组酶，并具有多层次的机制来抑制转座。我们描述了 DNA 结合模式的变化、蛋白质-DNA 复合物动力学的改变、单个氨基酸突变和模块化设计如何使 RAG 家族酶能够在真核生物的基因组中存活和传播。这些进展强调了通过比较基因组分析与结构生物学和生物化学相结合的视角来观察脊椎动物免疫进化可以获得的洞察力。
