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首页> 外文期刊>Biochemistry >Adaptive Mutations Alter Antibody Structure and Dynamics during Affinity Maturation
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Adaptive Mutations Alter Antibody Structure and Dynamics during Affinity Maturation

机译：适应性突变在亲和力成熟期间改变抗体结构和动力学

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摘要

While adaptive mutations can bestow new functions on proteins via the introduction or optimization of reactive centers, or other structural changes, a role for the optimization of protein dynamics also seems likely but has been more difficult to evaluate. Antibody (Ab) affinity maturation is an example of adaptive evolution wherein the adaptive mutations may be identified and Abs may be raised to specific targets that facilitate the characterization of protein dynamics. Here, we report the characterization of three affinity matured Abs that evolved from a common germline precursor to bind the chromophoric antigen (Ag), 8-methoxypyrene-1,3,6-trisulfonate (MPTS). In addition to characterizing the sequence, molecular recognition, and structure of each Ab, we characterized the dynamics of each complex by determining their mechanical response to an applied force via three-pulse photon echo peak shift (3PEPS) spectroscopy and deconvoluting the response into elastic, anelastic, and plastic components. We find that for one Ab, affinity maturation was accomplished via the introduction of a single functional group that mediates a direct contact with MPTS and results in a complex with little anelasticity or plasticity. In the other two cases, more mutations were introduced but none directly contact MPTS, and while their effects on structure are subtle, their effects on anelasticity and plasticity are significant, with the level of plasticity correlated with specificity, suggesting that the optimization of protein dynamics may have contributed to affinity maturation. A similar optimization of structure and dynamics may contribute to the evolution of other proteins.
机译：虽然自适应突变通过反应中心的引入或优化可以赋予蛋白质的新功能，或者其他结构变化，但蛋白质动态的优化作用也可能是更难以评估。抗体（AB）亲和力成熟是一种适应性演化的实例，其中可以鉴定自适应突变，并且可以向促进蛋白质动态表征的特定靶标升高。在此，我们报告了从常见的种系前体演变的三个亲和力成熟的吸收的表征，以结合发色抗原（Ag），8-甲氧基吡啶-1,3,6-三硫酸盐（MPTS）。除了表征每个AB的序列，分子识别和结构之外，我们通过通过三脉冲光子回波峰值移位（3PEPS）光谱法确定对施加的力的机械响应并将响应作用成弹性来表征每个复合物的动态。 ，无骨骼和塑料部件。我们发现，对于一个AB，亲和力成熟是通过引入单一官能团而介导与MPTS直接接触的官能团，并导致具有很小的复杂性或可塑性的复合物。在另外两种情况下，引入了更多的突变，但没有直接接触MPT，而它们对结构的影响是微妙的，它们对四组织性和塑性的影响是显着的，具有与特异性相关的可塑性水平，表明蛋白质动力学的优化可能有助于亲和力成熟。类似的结构和动力学优化可能有助于其他蛋白质的演变。

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  • 来源
    《Biochemistry》 |2015年第11期|共9页
  • 作者

    Adhikary Ramkrishna; Yu Wayne; Oda Masayuki; Walker Ross C.; Chen Tingjian; Stanfield Robyn L.; Wilson Ian A.; Zimmermann Joerg; Romesberg Floyd E.;

  • 作者单位

    Scripps Res Inst Dept Chem La Jolla CA 92037 USA;

    Scripps Res Inst Dept Chem La Jolla CA 92037 USA;

    Kyoto Prefectural Univ Grad Sch Life &

    Environm Sci Sakyo Ku Shimogamo Kyoto 6068522 Japan;

    Univ Calif San Diego Dept Chem &

    Biochem La Jolla CA 92093 USA;

    Scripps Res Inst Dept Chem La Jolla CA 92037 USA;

    Scripps Res Inst Dept Integrat Struct &

    Computat Biol La Jolla CA 92037 USA;

    Scripps Res Inst Dept Integrat Struct &

    Computat Biol La Jolla CA 92037 USA;

    Scripps Res Inst Dept Chem La Jolla CA 92037 USA;

    Scripps Res Inst Dept Chem La Jolla CA 92037 USA;

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  • 正文语种 eng
  • 中图分类 生物化学;
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