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首页> 外文期刊>Journal of Molecular Biology >Synonymous mutations and ribosome stalling can lead to altered folding pathways and distinct minima.
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Synonymous mutations and ribosome stalling can lead to altered folding pathways and distinct minima.

机译：同义突变和核糖体失速可导致折叠途径改变和明显的最小值。

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摘要

How can we understand a case in which a given amino acid sequence folds into structurally and functionally distinct molecules? Synonymous single-nucleotide polymorphisms in the MDR1 (multidrug resistance 1 or ABCB1) gene involving frequent-to-rare codon substitutions lead to identical protein sequences. Remarkably, these alternative sequences give a protein product with similar but different structures and functions. Here, we propose that long-enough ribosomal pause time scales may lead to alternate folding pathways and distinct minima on the folding free energy surface. While the conformational and functional differences between the native and alternate states may be minor, the MDR1 case illustrates that the barriers may nevertheless constitute sufficiently high hurdles in physiological time scales, leading to kinetically trapped states with altered structures and functions. Different folding pathways leading to conformationally similar trapped states may be due to swapping of (fairly symmetric) segments. Domain swapping is more likely in the no-pause case in which the chain elongates and folds simultaneously; on the other hand, sufficiently long pause times between such segments may be expected to lessen the chances of swapping events. Here, we review the literature in this light.
机译：我们如何理解给定氨基酸序列折叠成结构和功能上不同的分子的情况？ MDR1（多药耐药性1或ABCB1）基因中的同义单核苷酸多态性涉及到罕见的密码子替换，导致相同的蛋白质序列。值得注意的是，这些替代序列使蛋白质产物具有相似但不同的结构和功能。在这里，我们提出足够长的核糖体停顿时间尺度可能导致交替的折叠途径和折叠自由能表面上的明显最小值。尽管原始状态和替代状态之间的构象和功能差异可能很小，但MDR1案例说明，这些障碍可能仍构成生理时标上足够高的障碍，从而导致结构和功能发生变化的动力学陷阱态。导致构象相似的捕获状态的不同折叠途径可能是由于（相当对称）区段的交换。在无暂停的情况下，链同时伸长和折叠的情况下，域交换更可能发生;另一方面，可以期望在这些段之间足够长的暂停时间来减少交换事件的机会。在这里，我们从这个角度回顾文献。

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