Abstract

Lamellar ichthyosis (LI) is a rare inherited disease where affected infants present a extensive skin scaling characterized by hyperkeratosis. Inherited mutations in the Transglutaminase 1 (TGM1) protein is one of the known causative genetic factor for the LI. The main objective of this study is to explore the impact of LI causative missense mutations on the structural and stability aspects of TGM1 protein using structural modeling, molecular docking and molecular dynamics approaches. By testing all LI causative TMG1 mutations against multiple stability prediction methods, we found that L362R and L388P mutations positioned in the Transglut_core domain were most destabilizing to the stability of TGM1 protein. These 2 mutations were 3D protein modeled and further analyzed by molecular docking and dynamic simulation methods. Molecular docking of these TGM1 mutant structures with chitosan, a natural polyphenolic compound and known inducer for transglutaminase enzyme, has shown stable molecular interactions between the native TGM1-chitosan and TGM1(L388P)-chitosan complex, when compared to the TGM1(L362R)-chitosan complex. Interestingly, molecular dynamics analysis have also yielded similar findings, where L388P-chitosan complex is shown to develop B-sheets and attain better stability, whereas TGM1-L362R complex possessed coils over the simulation period, pointing its highly destabilizing behavior on the protein structure. This study concludes that missense mutations in Transglut_core domain of the TGM1 are deleterious to the stability and structural changes of TGM1 protein and also suggest that chitosan molecule could act as a natural activator against few pathogenic TGM1 mutations.

Communicated by Ramaswamy H. Sarma

摘要

层状鱼鳞病 (LI) 是一种罕见的遗传性疾病，受影响的婴儿会出现以角化过度为特征的广泛皮肤脱屑。转谷氨酰胺酶 1 (TGM1) 蛋白的遗传突变是已知的 LI 致病遗传因素之一。本研究的主要目的是利用结构建模、分子对接和分子动力学方法探索 LI 致病错义突变对 TGM1 蛋白结构和稳定性方面的影响。通过针对多种稳定性预测方法测试所有 LI 致病 TMG1 突变，我们发现位于 Transglut_core 结构域的 L362R 和 L388P 突变对 TGM1 蛋白的稳定性最不稳定。这 2 个突变被 3D 蛋白质建模，并通过分子对接和动态模拟方法进一步分析。与 TGM1(L362R) 相比，这些 TGM1 突变体结构与壳聚糖（一种天然多酚化合物和已知的转谷氨酰胺酶诱导剂）的分子对接显示了天然 TGM1-壳聚糖和 TGM1(L388P)-壳聚糖复合物之间的稳定分子相互作用。壳聚糖复合物。有趣的是，分子动力学分析也产生了类似的发现，其中 L388P-壳聚糖复合物显示出 B-折叠并获得更好的稳定性，而 TGM1-L362R 复合物在模拟期间具有线圈，表明其对蛋白质结构的高度不稳定行为。

由 Ramaswamy H. Sarma 传达