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采用三维同源建模技术对人类溶质载体 SLC26 阴离子转运蛋白病致病突变进行分子分析。

Molecular analysis of human solute carrier SLC26 anion transporter disease-causing mutations using 3-dimensional homology modeling.

机构信息

Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

出版信息

Biochim Biophys Acta Biomembr. 2017 Dec;1859(12):2420-2434. doi: 10.1016/j.bbamem.2017.09.016. Epub 2017 Sep 21.

Abstract

The availability of the first crystal structure of a bacterial member (SLC26Dg) of the solute carrier SLC26 family of anion transporters has allowed us to create 3-dimensional models of all 10 human members (SLC26A1-A11, A10 being a pseudogene) of these membrane proteins using the Phyre2 bioinformatic tool. The homology modeling predicted that the SLC26 human proteins, like the SLC26Dg template, all consist of 14 transmembrane segments (TM) arranged in a 7+7 inverted topology with the amino-termini of two half-helices (TM3 and 10) facing each other in the centre of the protein to create the anion-binding site, linked to a C-terminal cytosolic sulfate transporter anti-sigma factor antagonist (STAS) domain. A plethora of human diseases are associated with mutations in the genes encoding human SLC26 transporters, including chondrodysplasias with varying severity in SLC26A2 (50 mutations, 27 point mutations), congenital chloride-losing diarrhea in SLC26A3 (70 mutations, 31 point mutations) and Pendred Syndrome or deafness autosomal recessive type 4 in SLC26A4 (~500 mutations, 203 point mutations). We have localized all of these point mutations in the 3-dimensional structures of the respective SLC26A2, A3 and A4 proteins and systematically analyzed their effect on protein structure. While most disease-causing mutations may cause folding defects resulting in impaired trafficking of these membrane glycoproteins from the endoplasmic reticulum to the cell surface - as demonstrated in a number of functional expression studies - the modeling also revealed that a number of pathogenic mutations are localized to the anion-binding site, which may directly affect transport function.

摘要

第一个阴离子转运体溶质载体家族 SLC26 成员(SLC26Dg)的晶体结构的出现,使得我们能够使用 Phyre2 生物信息学工具创建所有 10 个人类成员(SLC26A1-A11,A10 是假基因)的 3 维模型。同源建模预测,SLC26 人类蛋白与 SLC26Dg 模板一样,都由 14 个跨膜段(TM)组成,以 7+7 反向拓扑排列,两个半环(TM3 和 10)的氨基末端相对,在蛋白质中心形成阴离子结合位点,并与 C 末端胞质硫酸盐转运反西格玛因子拮抗剂(STAS)结构域相连。大量人类疾病与编码人类 SLC26 转运蛋白的基因突变有关,包括 SLC26A2 中不同严重程度的软骨发育不良(50 个突变,27 个点突变)、SLC26A3 中的先天性氯丢失性腹泻(70 个突变,31 个点突变)和 Pendred 综合征或常染色体隐性遗传 4 型耳聋 SLC26A4(~500 个突变,203 个点突变)。我们已经将所有这些点突变定位在各自的 SLC26A2、A3 和 A4 蛋白的 3 维结构中,并系统地分析了它们对蛋白质结构的影响。虽然大多数致病突变可能导致折叠缺陷,从而使这些膜糖蛋白从内质网向细胞表面的运输受损——正如许多功能表达研究所示——建模还表明,一些致病性突变定位于阴离子结合位点,这可能直接影响转运功能。

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