Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390.
Biophysics University of Texas Southwestern Medical Center, Dallas, TX 75390.
J Lipid Res. 2013 Aug;54(8):2144-2152. doi: 10.1194/jlr.M037218. Epub 2013 May 29.
Ubxd8, a multidomain protein sensor for long-chain unsaturated fatty acids (FAs), plays a crucial role to maintain cellular homeostasis of FAs. Ubxd8 polymerizes upon interaction with long-chain unsaturated FAs, but the molecular mechanism involved in this polymerization remains unclear. Here we report that the UAS domain of Ubxd8 mediates this polymerization. We show that a positively charged surface area in the domain is required for the reaction. Mutations changing the positively charged residues in this area to glutamates prevented long-chain unsaturated FAs from inducing oligomerization of Ubxd8. Consequently, the mutant protein no longer responded to regulation by long-chain unsaturated FAs in cultured cells. Long-chain unsaturated FAs also induced polymerization of Fas-associated factor 1 (FAF1), the only other mammalian protein that contains a UAS domain homologous to that of Ubxd8. These results provide further insights into protein-FA interactions by identifying the UAS domain as a motif interacting with long-chain unsaturated FAs.
Ubxd8 是一种多结构域蛋白传感器，可感应长链不饱和脂肪酸（FAs），在维持细胞内 FA 稳态方面发挥着关键作用。Ubxd8 与长链不饱和 FA 相互作用后会发生聚合，但这一聚合过程中的具体分子机制仍不清楚。本研究报道 Ubxd8 的 UAS 结构域介导了这一聚合过程。我们发现该结构域中的正电荷表面积对于这一反应是必需的。将该区域中的正电荷残基突变为谷氨酸会阻止长链不饱和 FA 诱导 Ubxd8 寡聚化。因此，突变蛋白不再响应长链不饱和 FA 在培养细胞中的调控。长链不饱和 FA 还会诱导 Fas 相关因子 1（FAF1）聚合，FAF1 是唯一含有与 Ubxd8 同源的 UAS 结构域的哺乳动物蛋白。这些结果通过鉴定 UAS 结构域为与长链不饱和 FA 相互作用的基序，进一步深入了解了蛋白与 FA 的相互作用。
