Myosin VI is involved in many cellular processes ranging from endocytosis to transcription. This multifunctional potential is achieved through alternative isoform splicing and through interactions of myosin VI with a diverse network of binding partners. However, the interplay between these two modes of regulation remains unexplored. To this end, we compared two different binding partners and their interactions with myosin VI by exploring the kinetic properties of recombinant proteins and their distribution in mammalian cells using fluorescence imaging. We found that selectivity for these binding partners is achieved through a high-affinity motif and a low-affinity motif within myosin VI. These two motifs allow competition among partners for myosin VI. Exploring how this competition affects the activity of nuclear myosin VI, we demonstrate the impact of a concentration-driven interaction with the low-affinity binding partner DAB2, finding that this interaction blocks the ability of nuclear myosin VI to bind DNA and its transcriptional activity in vitro We conclude that loss of DAB2, a tumor suppressor, may enhance myosin VI-mediated transcription. We propose that the frequent loss of specific myosin VI partner proteins during the onset of cancer leads to a higher level of nuclear myosin VI activity.

中文翻译：

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肌球蛋白 VI 中两个高亲和力和低亲和力蛋白结合位点之间的竞争控制其细胞功能。

肌球蛋白 VI 参与从内吞作用到转录的许多细胞过程。这种多功能潜力是通过替代异构体剪接以及通过肌球蛋白 VI 与多种结合伙伴网络的相互作用来实现的。然而，这两种监管模式之间的相互作用仍未得到探索。为此，我们通过使用荧光成像探索重组蛋白的动力学特性及其在哺乳动物细胞中的分布，比较了两种不同的结合伙伴及其与肌球蛋白 VI 的相互作用。我们发现这些结合伙伴的选择性是通过肌球蛋白 VI 内的高亲和力基序和低亲和力基序实现的。这两个基序允许合作伙伴之间竞争肌球蛋白 VI。探索这种竞争如何影响核肌球蛋白 VI 的活性，我们证明了与低亲和力结合伙伴 DAB2 的浓度驱动相互作用的影响，发现这种相互作用阻断了核肌球蛋白 VI 结合 DNA 的能力及其体外转录活性 我们得出结论，DAB2 的丧失，一种肿瘤抑制因子，可能增强肌球蛋白 VI 介导的转录。我们建议在癌症发作期间频繁丢失特定的肌球蛋白 VI 伴侣蛋白会导致更高水平的核肌球蛋白 VI 活性。