THE CDR1 SEQUENCES OF A MAJOR PROPORTION OF HUMAN GERMLINE IG V-H GENES ARE INHERENTLY SUSCEPTIBLE TO AMINO-ACID REPLACEMENT
THE CDR1 SEQUENCES OF A MAJOR PROPORTION OF HUMAN GERMLINE IG V-H GENES ARE INHERENTLY SUSCEPTIBLE TO AMINO-ACID REPLACEMENT
复制标题
DOI：
10.1016/0167-5699(94)90175-9
复制
发表时间：
1994-08-01
期刊：
影响因子：
--
通讯作者：
CASALI, P
中科院分区：
文献类型：
--
作者：
CHANG, B;CASALI, P
已知抗原选择抗体的可变（V）基因在编码抗原接触互补决定区（CDR）的序列中比在编码“结构”框架区（FR）的序列中表现出更高频率的氨基酸置换突变。在这里，Bernard Chang和Paolo Casali分析了人种系IG V-H和V-L基因密码子组成的区域差异对基因产物（即抗体分子的抗原结合位点）中置换突变频率的区域差异的影响。该分析表明，CDR和FR序列在其对氨基酸置换的固有易感性方面可以显著不同，只要有任何单个核苷酸变化。因此，所分析的所有IG V-H基因的CDR序列包含比随机序列预期的更高频率的易受置换突变影响的密码子。相反，FR序列包含比预期更不易于发生置换突变的密码子。在含有CDR的IG V-基因区段的整个编码序列中核苷酸变化的随机累积固有地比相应的FR更易于置换突变，这将不可避免地在CDR中产生比在FR中更高的氨基酸置换率。这将为抗原选择提供高变性的可育结构底物，同时仍保持FR的结构完整性。
The variable (V) genes of antigen-selected antibodies are known to exhibit a higher frequency of amino acid replacement mutations in the sequences encoding the antigen-contacting complementarity-determining regions (CDRs) than in those encoding the 'structural' framework regions (FRs). Here, Bernard Chang and Paolo Casali analyse the impact of regional differences in the codon composition of human germline Ig V-H and V-L genes on regional differences in the frequency of replacement mutations in the gene products (i.e. the antigen-binding sites of antibody molecules). This analysis reveals that CDR and FR sequences can differ significantly in their inherent susceptibility to amino acid replacement given any single nucleotide change. Thus, the CDR sequences of all the Ig V-H genes analysed comprise a higher frequency of codons susceptible to replacement mutations than would be expected for a random sequence. Conversely the FR sequences comprise codons less susceptible to replacement mutations than expected. Random accumulation of nucleotide changes throughout the coding sequence of an Ig V-gene segment containing CDRs inherently more prone to replacement mutations than the respective FRs would inevitably yield a higher rate of amino acid replacements in the CDRs than in the FRs. This would provide a fertile structural substrate of hypervariability for antigen selection while still maintaining the structural integrity of the FRs.