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首页> 外文期刊>Biochimica et biophysica acta. Biomembranes >Inhibition of mitochondrial UCP1 and UCP3 by purine nucleotides and phosphate
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Inhibition of mitochondrial UCP1 and UCP3 by purine nucleotides and phosphate

机译：嘌呤核苷酸和磷酸盐抑制线粒体UCP1和UCP3

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Mitochondrial membrane uncoupling protein 3 (UCP3) is not only expressed in skeletal muscle and heart, but also in brown adipose tissue (BAT) alongside UCP1, which facilitates a proton leak to support non-shivering thermogenesis. In contrast to UCP1, the transport function and molecular mechanism of UCP3 regulation are poorly investigated, although it is generally agreed upon that UCP3, analogous to UCP1, transports protons, is activated by free fatty acids (FFAs) and is inhibited by purine nucleotides (PNs). Because the presence of two similar uncoupling proteins in BAT is surprising, we hypothesized that UCP1 and UCP3 are differently regulated, which may lead to differences in their functions. By combining atomic force microscopy and electrophysiological measurements of recombinant proteins reconstituted in planar bilayer membranes, we compared the level of protein activity with the bond lifetimes between UCPs and PNs. Our data revealed that, in contrast to UCP1, UCP3 can be fully inhibited by all PNs and IC50 increases with a decrease in PN-phosphorylation. Experiments with mutant proteins demonstrated that the conserved arginines in the PN-binding pocket are involved in the inhibition of UCP1 and UCP3 to different extents. Fatty acids compete with all PNs bound to UCP1, but only with ATP bound to UCP3. We identified phosphate as a novel inhibitor of UCP3 and UCP1, which acts independently of PNs. The differences in molecular mechanisms of the inhibition between the highly homologous transporters UCP1 and UCP3 indicate that UCP3 has adapted to fulfill a different role and possibly another transport function in BAT.
机译：线粒体膜解耦蛋白3（UCP3）不仅在骨骼肌和心脏中表达，而且在棕色脂肪组织（BAT）旁边的UCP1中，这有利于质子泄漏来支持不颤动的热生成。与UCP1相比，UCP3调节的运输功能和分子机制较差，尽管通常通过游离脂肪酸（FFA）来激活UCP3，类似于UCP1的UCP3，并被嘌呤核苷酸抑制（ PNS）。由于蝙蝠中两种类似的未偶联蛋白质存在令人惊讶的是，我们假设UCP1和UCP3不同调节，这可能导致其功能的差异。通过组合在平面双层膜中重构的重组蛋白的原子力显微镜和电生理学测量，我们将蛋白质活性水平与UCP和PNS之间的粘合寿命进行了比较。我们的数据显示，与UCP1相比，所有PNS和IC50可以完全抑制UCP3，并且IC50随着PN磷酸化的降低而增加。突变蛋白的实验证明了PN结合口袋中的保守精氨酸涉及UCP1和UCP3对不同范围的抑制作用。脂肪酸与所有与UCP1结合的PNS竞争，但只有ATP与UCP3结合。我们将磷酸盐鉴定为UCP3和UCP1的新型抑制剂，其独立于PNS作用。高同同源转运蛋白UCP1和UCP3之间的抑制分子机制的差异表明，UCP3适于满足不同的作用和可能在蝙蝠中的另一个运输功能。

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