Differences in potential for amino acid change after mutation reveals distinct strategies for κ and λ light-chain variation
Differences in potential for amino acid change after mutation reveals distinct strategies for κ and λ light-chain variation
复制标题
DOI：
10.1073/pnas.0607581103
复制
发表时间：
2006-10-24
影响因子：
11.1
通讯作者：
Shlomchik, Mark J.
中科院分区：
文献类型：
--
作者：
Hershberg, Uri;Shlomchik, Mark J.
B细胞在其V基因的高突变率下产生多样但功能性的克隆。已经提出，由于多样化和保持完整性的相反需求，重链和轻链的V基因已经进化为过表达与框架（FW）区相比在其互补决定区（CDR）中易于发生氨基酸变化的密码子。我们分析了重链和轻链（K和A）的种系V基因，比较了种系V区CDR和FW的密码子，并与对照区进行了比较。我们发现在生殖系重链和A链中，CDR密码子易于发生替换突变，而在FW中，情况正好相反。此外，重链和A链中CDR和FW之间的差异是基于易于发生氨基酸非保守变化的密码子。相反，在生殖系K链中，CDR和FW中的密码子更容易发生置换突变。我们还表明，在免疫应答过程中的负选择是更敏感的非保守氨基酸取代比整体氨基酸的变化，证明了我们的分析的适用性，在免疫系统中的实时选择过程。生殖系K和A轻链对突变的潜在反应的差异表明，通过这两种不同进化的轻链类型，B细胞库包含两种不同的策略来平衡免疫应答中的多样性和稳定性。
B cells generate varied yet functional clones under high rates of mutation of their V genes. It has been proposed that as a result of the opposing demands of diversification and preservation of integrity, the V genes of heavy and light chains have evolved to overexpress codons prone to amino acid change in their complementarity determining regions (CDR) compared with the framework (FW) regions. We have analyzed the germ-line V genes of heavy and light chains (both K and A), comparing codons of CDR and FW of the germ-line V regions both to each other and to control regions. We found that in both germ-line heavy chains and A chains, CDR codons are prone to replacement mutations, whereas in the FW, the opposite is true. Furthermore, the difference between CDR and FW in heavy chains and A chains is based on codons that are prone to nonconservative changes of amino acid. In contrast, in germ-line K chains, the codons in both CDR and FW are more prone to replacement mutations. We also demonstrated that negative selection during immune responses is more sensitive to nonconservative amino acid substitutions than overall amino acid change, demonstrating the applicability of our analysis to real-time process of selection in the immune system. The differences in germ-line K and A light chains' potential reaction to mutation suggests that via these two differently evolved light-chain types, the B cell repertoire encompasses two different strategies to balance diversity and stability in an immune response.