Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
Department of Chemistry, Faculty of Science, King Mongkut's University of Technology Thonburi (KMUTT), Bang Mod, Thung Khru, Bangkok 10140, Thailand.
J Am Chem Soc. 2021 Sep 22;143(37):15271-15278. doi: 10.1021/jacs.1c06461. Epub 2021 Sep 8.
The human long interspersed nuclear element 1 (LINE1) has been implicated in numerous diseases and has been suggested to play a significant role in genetic evolution. Open reading frame 1 protein (ORF1p) is one of the two proteins encoded in this self-replicating mobile genetic element, both of which are essential for retrotransposition. The structure of the three-stranded coiled-coil domain of ORF1p was recently solved and showed the presence of tris-cysteine layers in the interior of the coiled-coil that could function as metal binding sites. Here, we demonstrate that ORF1p binds Pb(II). We designed a model peptide, L16CL23C, to mimic two of the ORF1p Cys layers and crystallized the peptide both as the apo-form and in the presence of Pb(II). Structural comparison of the ORF1p with apo-(L16CL23C) shows very similar Cys layers, preorganized for Pb(II) binding. We propose that exposure to heavy metals, such as lead, could influence directly the structural parameters of ORF1p and thus impact the overall LINE1 retrotransposition frequency, directly relating heavy metal exposure to genetic modification.
人类长散布核元件 1（LINE1）与许多疾病有关，并被认为在遗传进化中发挥了重要作用。开放阅读框 1 蛋白（ORF1p）是这个自我复制的移动遗传元件编码的两种蛋白之一，两者对于逆转录转座都是必不可少的。ORF1p 的三股螺旋卷曲螺旋结构域的结构最近已被解决，并显示卷曲螺旋内部存在三半胱氨酸层，可作为金属结合位点。在这里，我们证明了 ORF1p 结合 Pb(II)。我们设计了一个模型肽 L16CL23C，以模拟 ORF1p 的两个 Cys 层，并对该肽进行了apo 形式和 Pb(II)存在下的结晶。ORF1p 与 apo-(L16CL23C)的结构比较显示出非常相似的 Cys 层，这些层预先形成了 Pb(II)的结合。我们提出，暴露于重金属（如铅）可能会直接影响 ORF1p 的结构参数，从而影响 LINE1 逆转录转座的整体频率，将重金属暴露与遗传修饰直接联系起来。
