University of Southampton, Faculty of Medicine, Southampton SO16 6YD, UK.
Slovak Academy of Sciences, Centre of Biosciences, 840 05 Bratislava, Slovak Republic.
Nucleic Acids Res. 2024 Feb 9;52(3):1090-1106. doi: 10.1093/nar/gkad1161.
Exonic sequences contain both protein-coding and RNA splicing information but the interplay of the protein and splicing code is complex and poorly understood. Here, we have studied traditional and auxiliary splicing codes of human exons that encode residues coordinating two essential divalent metals at the opposite ends of the Irving-Williams series, a universal order of relative stabilities of metal-organic complexes. We show that exons encoding Zn2+-coordinating amino acids are supported much less by the auxiliary splicing motifs than exons coordinating Ca2+. The handicap of the former is compensated by stronger splice sites and uridine-richer polypyrimidine tracts, except for position -3 relative to 3' splice junctions. However, both Ca2+ and Zn2+ exons exhibit close-to-constitutive splicing in multiple tissues, consistent with their critical importance for metalloprotein function and a relatively small fraction of expendable, alternatively spliced exons. These results indicate that constraints imposed by metal coordination spheres on RNA splicing have been efficiently overcome by the plasticity of exon-intron architecture to ensure adequate metalloprotein expression.
外显子序列既包含蛋白质编码信息，也包含 RNA 剪接信息，但蛋白质和剪接代码之间的相互作用非常复杂，目前人们对此了解甚少。在这里，我们研究了人类外显子的传统和辅助剪接代码，这些外显子编码的残基在 Irving-Williams 系列的两端协调两种必需的二价金属，该系列是有机金属配合物相对稳定性的通用顺序。我们发现，与编码 Ca2+的外显子相比，编码 Zn2+配位氨基酸的外显子辅助剪接基序的支持度要低得多。前者的障碍通过更强的剪接位点和富含尿嘧啶的多嘧啶序列得到了补偿，但 3' 剪接接头处的位置 -3 除外。然而，Ca2+ 和 Zn2+ 外显子在多种组织中均表现出近乎组成性剪接，这与其对金属蛋白酶功能的重要性以及相对较小比例的可选择剪接外显子一致。这些结果表明，金属配位球对 RNA 剪接的限制已被外显子-内含子结构的可塑性有效地克服，以确保充足的金属蛋白酶表达。
