Demkiv Andrey O, Toledo-Patiño Saacnicteh, Medina-Carmona Encarnación, Berg Andrej, Pinto Gaspar P, Parracino Antonietta, Sanchez-Ruiz Jose M, Hengge Alvan C, Laurino Paola, Longo Liam M, Kamerlin Shina Caroline Lynn
Department of Chemistry-BMC, Uppsala University, Uppsala S-751 23, Sweden.
Protein Engineering and Evolution Unit, Okinawa Institute of Science and Technology, Graduate University (OIST), Okinawa 904-0495, Japan.
Mol Biol Evol. 2025 Apr 1;42(4). doi: 10.1093/molbev/msaf055.
At the heart of many nucleoside triphosphatases is a conserved phosphate-binding sequence motif. A current model of early enzyme evolution proposes that this six to eight residue motif could have sparked the emergence of the very first nucleoside triphosphatases-a striking example of evolutionary continuity from simple beginnings, if true. To test this provocative model, seven disembodied Walker A-derived peptides were extensively computationally characterized. Although dynamic flickers of nest-like conformations were observed, significant structural similarity between the situated peptide and its disembodied counterpart was not detected. Simulations suggest that phosphate binding is nonspecific, with a preference for GTP over orthophosphate. Control peptides with the same amino acid composition but different sequences and situated conformations behaved similarly to the Walker A peptides, revealing no indication that the Walker A sequence is privileged as a disembodied peptide. We conclude that the evolutionary history of the P-loop NTPase family is unlikely to have started with a disembodied Walker A peptide in an aqueous environment. The limits of evolutionary continuity for this protein family must be reconsidered. Finally, we argue that motifs such as the Walker A motif may represent incomplete or fragmentary molecular fossils-the true nature of which has been eroded by time.
许多核苷三磷酸酶的核心是一个保守的磷酸结合序列基序。当前关于早期酶进化的模型提出，这个由六到八个残基组成的基序可能引发了最早的核苷三磷酸酶的出现——如果这是真的，那将是一个从简单起源开始的进化连续性的显著例子。为了验证这个具有启发性的模型，对七个无实体的源自沃克A的肽段进行了广泛的计算表征。尽管观察到了巢状构象的动态闪烁，但未检测到处于特定位置的肽段与其无实体对应物之间存在显著的结构相似性。模拟结果表明，磷酸盐结合是非特异性的，相对于正磷酸盐而言更倾向于结合鸟苷三磷酸（GTP）。具有相同氨基酸组成但不同序列和特定构象的对照肽段与沃克A肽段表现相似，这表明没有迹象表明沃克A序列作为无实体肽段具有特殊优势。我们得出结论，P环NTP酶家族的进化历史不太可能始于水环境中无实体的沃克A肽段。必须重新考虑这个蛋白质家族进化连续性的限度。最后，我们认为诸如沃克A基序之类的基序可能代表不完整或碎片化的分子化石——其真实本质已随时间被侵蚀。
