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首页> 外文期刊>Cell cycle >Kinetic partitioning during de novo septin filament assembly creates a critical G1 'window of opportunity' for mutant septin function
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Kinetic partitioning during de novo septin filament assembly creates a critical G1 'window of opportunity' for mutant septin function

机译：从头分离蛋白丝组装过程中的动力学分配为突变蛋白的功能创造了关键的G1“机会之窗”

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摘要

Septin proteins form highly conserved cytoskeletal filaments composed of hetero-oligomers with strict subunit stoichiometry. Mutations within one hetero-oligomerization interface (the G interface) bias the mutant septin toward conformations that are incompatible with filament assembly, causing disease in humans and, in budding yeast cells, temperature-sensitive defects in cytokinesis. We previously found that, when the amount of other hetero-oligomerization partners is limiting, wild-type and G interface-mutant alleles of a given yeast septin compete along parallel but distinct folding pathways for occupancy of a limited number of positions within septin hetero-octamers. Here, we synthesize a mathematical model that outlines the requirements for this phenomenon: if a wild-type septin traverses a folding pathway that includes a single rate-limiting folding step, the acquisition by a mutant septin of additional slow folding steps creates an initially large disparity between wild-type and mutant in the cellular concentrations of oligomerization-competent monomers. When the 2 alleles are co-expressed, this kinetic disparity results in mutant exclusion from hetero-oligomers, even when the folded mutant monomer is oligomerization-competent. To test this model experimentally, we first visualize the kinetic delay in mutant oligomerization in living cells, and then narrow or widen the window of opportunity for mutant septin oligomerization by altering the length of the G1 phase of the yeast cell cycle, and observe the predicted exacerbation or suppression, respectively, of mutant cellular phenotypes. These findings reveal a fundamental kinetic principle governing in vivo assembly of multiprotein complexes, independent of the ability of the subunits to associate with each other.
机译：Septin蛋白形成高度保守的细胞骨架细丝，该细丝由具有严格亚基化学计量的杂合寡聚物组成。一个杂合寡聚界面（G界面）内的突变会将突变菌素偏向与细丝装配不相容的构象，从而导致人类疾病，并在发芽的酵母细胞中引起胞质分裂的温度敏感性缺陷。我们先前发现，当其他异源寡聚伙伴的数量受到限制时，给定酵母菌隔蛋白的野生型和G界面突变等位基因会沿着平行但独特的折叠途径竞争，从而在异菌素异源寡聚核苷酸中占据有限数量的位置八度。在这里，我们综合了一个数学模型，概述了对此现象的要求：如果野生型Septin穿过包含单个限速折叠步骤的折叠路径，则突变Septin对其他缓慢折叠步骤的获取会产生一个较大的初始值寡聚能力单体的细胞浓度中野生型和突变型之间的差异。当两个等位基因共表达时，即使折叠的突变体单体具有低聚能力，该动力学差异也会导致突变体被异源寡聚体排斥。为了通过实验测试该模型，我们首先观察活细胞中突变体寡聚化的动力学延迟，然后通过改变酵母细胞周期的G1期长度来缩小或加宽突变体Septin寡聚化的机会窗口，并观察预测的突变细胞表型的恶化或抑制。这些发现揭示了支配多蛋白复合物在体内组装的基本动力学原理，而与亚基彼此缔合的能力无关。

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