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Novel insights into the structure and transport mechanisms of TAPT1
bioRxiv - Biochemistry Pub Date : 2020-05-23 , DOI: 10.1101/2020.05.18.099887
Md Sorwer Alam Parvez , Mohammad Mahfujur Rahman , Md Niaz Morshed , Dolilur Rahman , Saeed Anwar , Paul J. Coucke , Mohammad Jakir Hosen

Transmembrane anterior-posterior transformation protein 1 (TAPT1), encoded by the TAPT1 gene expressed in the basal ciliary body, plays a crucial role in cilia formation as well as axial skeletal patterning. Mutations in this gene have been reported to cause several ciliopathies and osteo-related diseases. Unfortunately, the cellular and molecular pathogenic mechanisms are still unclear also due to the lack of X-ray crystallographic structure and further characterization of TAPT1 protein. In this study, we attempted to characterize this protein by in silico techniques. A 3D structure of TAPT1 was generated by the ab initio method, which was further used for the analysis of the substrate-binding site, to determine pore size and for the prediction of the possible substrate(s). Validation by using different software packages revealed a reliable 3D model of TAPT1. Topology modeling revealed that TAPT1 has eight transmembrane helices with a total number of 27 helices in secondary structure. The amino acid residues H235, R323, K443, N446, S447, L450, K453, S454, Y457, K511, N513, D533, K535, D536, and T538 were found to form the pore surface as well as involved in the binding interaction with the substrate(s). This study predicted flavonoids as the possible substrate for TAPT1, which could further be confirmed by ingenuity pathway analysis. Moreover, our analysis indicated that TAPT1 might localize in the mitochondrial membrane in addition to the ciliary basal body. Our study gives novel insights for TAPT1 structure and its function.

中文翻译:

对TAPT1的结构和转运机制的新颖见解

跨膜前后转化蛋白1(TAPT1),由在基底睫状体中表达的TAPT1基因编码,在纤毛形成和轴向骨骼结构中起关键作用。据报道该基因的突变会引起几种纤毛病和与骨有关的疾病。不幸的是,由于缺乏X射线晶体学结构和TAPT1蛋白的进一步表征,细胞和分子的致病机理仍不清楚。在这项研究中,我们试图通过计算机技术表征这种蛋白质。通过从头算生成TAPT1的3D结构,该结构进一步用于分析底物结合位点,确定孔径并预测可能的底物。通过使用不同的软件包进行的验证揭示了TAPT1的可靠3D模型。拓扑建模显示,TAPT1具有八个跨膜螺旋,二级结构中共有27个螺旋。发现氨基酸残基H235,R323,K443,N446,S447,L450,K453,S454,Y457,K511,N513,D533,K535,D536和T538形成了孔表面并参与了与基板。这项研究预测类黄酮可能是TAPT1的可能底物,可以通过机敏途径分析进一步证实。此外,我们的分析表明,TAPT1可能除了睫状基底体外还位于线粒体膜上。我们的研究为TAPT1结构及其功能提供了新颖的见解。拓扑建模显示,TAPT1具有八个跨膜螺旋,二级结构中共有27个螺旋。发现氨基酸残基H235,R323,K443,N446,S447,L450,K453,S454,Y457,K511,N513,D533,K535,D536和T538形成了孔表面并参与了与基板。这项研究预测类黄酮可能是TAPT1的可能底物,可以通过机敏途径分析进一步证实。此外,我们的分析表明,TAPT1可能除睫状体基底体外还位于线粒体膜中。我们的研究为TAPT1结构及其功能提供了新颖的见解。拓扑建模显示,TAPT1具有八个跨膜螺旋,二级结构中共有27个螺旋。发现氨基酸残基H235,R323,K443,N446,S447,L450,K453,S454,Y457,K511,N513,D533,K535,D536和T538形成了孔表面并参与了与基板。这项研究预测类黄酮可能是TAPT1的可能底物,可以通过机敏途径分析进一步证实。此外,我们的分析表明,TAPT1可能除睫状体基底体外还位于线粒体膜中。我们的研究为TAPT1结构及其功能提供了新颖的见解。发现T538和T538形成孔表面并参与与底物的结合相互作用。这项研究预测类黄酮可能是TAPT1的可能底物,可以通过机敏途径分析进一步证实。此外,我们的分析表明,TAPT1可能除睫状体基底体外还位于线粒体膜中。我们的研究为TAPT1结构及其功能提供了新颖的见解。发现T538和T538形成孔表面并参与与底物的结合相互作用。这项研究预测类黄酮可能是TAPT1的可能底物,可以通过机敏途径分析进一步证实。此外,我们的分析表明,TAPT1可能除了睫状基底体外还位于线粒体膜上。我们的研究为TAPT1结构及其功能提供了新颖的见解。
更新日期:2020-05-23
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