Human sodium-independent glucose cotransporter 1 (hGLUT1) has been studied for its tetramerization and multimerization at the cell surface. Homozygous or compound heterozygous mutations in hGLUT1 elicit GLUT1-deficiency syndrome (GLUT1-DS), a metabolic disorder, which results in impaired glucose transport into the brain. The reduced cell surface expression or loss of function have been shown for some GLUT1 mutants. However, the mechanism by which deleterious mutations affect protein structure, conformational stability and GLUT1 oligomerization is not known and require investigation. In this review, we combined previous knowledge of GLUT1 mutations with hGLUT1 crystal structure to analyze native interactions and several natural single-point mutations. The modeling of native hGLUT1 structure confirmed the roles of native residues in forming a range of side-chain interactions. Interestingly, the modeled mutants pointed to the formation of a variety of non-native novel interactions, altering interaction networks and potentially eliciting protein misfolding. Self-aggregation of the last part of hGLUT1 was predicted using protein aggregation prediction tool. Furthermore, an increase in aggregation potential in the aggregation-prone regions was estimated for several mutants suggesting increased aggregation of misfolded protein. Protein stability change analysis predicted that GLUT1 mutant proteins are unstable. Combining GLUT1 oligomerization behavior with our modeling, aggregation prediction, and protein stability analyses, this work provides state-of-the-art view of GLUT1 genetic mutations that could destabilize native interactions, generate novel interactions, trigger protein misfolding, and enhance protein aggregation in a disease state.

中文翻译：

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对导致GLUT1缺乏综合症的GLUT1遗传变异中蛋白质稳定性和自聚集的机械性见解。

已经研究了人类钠依赖性葡萄糖共转运蛋白1（hGLUT1）在细胞表面的四聚作用和多聚作用。hGLUT1中的纯合子或复合杂合子突变会引起GLUT1缺乏症候群（GLUT1-DS），这是一种代谢紊乱，导致葡萄糖向大脑的转运受损。对于某些GLUT1突变体，已经证明细胞表面表达降低或功能丧失。但是，有害突变影响蛋白质结构，构象稳定性和GLUT1寡聚化的机制尚不清楚，需要进行研究。在这篇综述中，我们结合了先前对GLUT1突变和hGLUT1晶体结构的了解，以分析自然相互作用和几个自然单点突变。天然hGLUT1结构的建模证实了天然残基在形成一系列侧链相互作用中的作用。有趣的是，建模的突变体指出了各种非天然新颖相互作用的形成，改变了相互作用网络并可能引起蛋白质错误折叠。使用蛋白质聚集预测工具预测了hGLUT1的最后一部分的自聚集。此外，估计了几个突变体在倾向于聚集的区域中聚集潜力的增加，表明错误折叠的蛋白质的聚集增加。蛋白质稳定性变化分析预测，GLUT1突变蛋白不稳定。将GLUT1低聚行为与我们的建模，聚集预测和蛋白质稳定性分析相结合，