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首页> 外文期刊>Journal of Molecular Biology >NADPH is an allosteric regulator of HSCARG.
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NADPH is an allosteric regulator of HSCARG.

机译：NADPH是HSCARG的变构调节剂。

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摘要

NADP(H) is an important cofactor that controls many fundamental cellular processes. We have determined the crystal structure of HSCARG, a novel NADPH sensor, and found that it forms an asymmetrical dimer with only one subunit occupied by an NADPH molecule, and the two subunits have dramatically different conformations. To study the role of NADPH in affecting the structure and function of HSCARG, here, we constructed a series of HSCARG mutants to abolish NADPH binding ability. Protein structures of two mutants, R37A and Y81A, were solved by X-ray crystallography. The dimerization of wild-type and mutant HSCARG was studied by dynamic light scattering. Differences between the function of wild-type and mutant HSCARG were also compared. Our results show that binding of NADPH is necessary for HSCARG to form a stable asymmetric dimer. The conformation of the monomeric mutants was similar to that of NADPH-bound Molecule I in wild-type HSCARG, although some conformational changes were found in the NADPH bindingsite. Furthermore, we also noticed that abolition of NADPH binding ability changes the distribution of HSCARG in the cell and that these mutants without NADPH are more strongly associated with argininosuccinate synthetase as compared with wild-type HSCARG. These data suggest that NADPH functions as an allosteric regulator of the structure and function of HSCARG. In response to the changes in the NADPH/NADP(+) ratio within cells, HSCARG, as a redox sensor, associates and dissociates with NADPH to form a new dynamic equilibrium. This equilibrium, in turn, will tip the dimerization balance of the protein molecule and consequently controls the regulatory function of HSCARG.
机译：NADP（H）是控制许多基本细胞过程的重要辅助因子。我们已经确定了新型NADPH传感器HSCARG的晶体结构，并发现它形成了一个不对称二聚体，其中只有一个亚基被NADPH分子占据，并且这两个亚基的构象有很大不同。为了研究NADPH在影响HSCARG的结构和功能中的作用，在这里，我们构建了一系列HSCARG突变体以消除NADPH的结合能力。 X射线晶体学分析了两个突变体R37A和Y81A的蛋白质结构。通过动态光散射研究了野生型和突变型HSCARG的二聚化。还比较了野生型和突变型HSCARG的功能差异。我们的结果表明，NADPH的结合对于HSCARG形成稳定的不对称二聚体是必需的。尽管在NADPH结合位点发现了一些构象变化，但单体突变体的构象与野生型HSCARG中与NADPH结合的分子I的构象相似。此外，我们还注意到，取消NADPH结合能力会改变HSCARG在细胞中的分布，并且与野生型HSCARG相比，这些没有NADPH的突变体与精氨琥珀酸合成酶的关联更紧密。这些数据表明NADPH作为HSCARG的结构和功能的变构调节剂。响应细胞内NADPH / NADP（+）比率的变化，HSCARG作为氧化还原传感器与NADPH缔合和解离，形成新的动态平衡。反过来，这种平衡将使蛋白质分子的二聚平衡达到平衡，从而控制HSCARG的调节功能。

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