Three-dimensional structure of beta-cell-specific zinc transporter, ZnT-8, predicted from the type 2 diabetes-associated gene variant SLC30A8 R325W.
Three-dimensional structure of beta-cell-specific zinc transporter, ZnT-8, predicted from the type 2 diabetes-associated gene variant SLC30A8 R325W.
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DOI：
10.1186/1758-5996-2-33
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发表时间：
2010-06-05
影响因子：
4.8
通讯作者：
Weijers RN
中科院分区：
文献类型：
--
作者：
Weijers RN
我们检测了R325W突变对β细胞特异性Zn2+（锌）转运体ZnT-8三维（3D）结构的影响。基于已知的大肠杆菌（e.c oli）锌转运蛋白YiiP晶体结构，以3.8 Å分辨率进行同源性建模，构建了人类ZnT-8蛋白c端结构域模型。同源二聚体ZnT-8蛋白结构呈y形结构，Arg325位于该基序的最终底部，距离跨膜结构域接合点约13.5 Å。人类ZnT-8蛋白的c端结构域序列与大肠杆菌锌转运蛋白YiiP具有12.3%的同源性和39.5%的同源性，同源性为51.8%。同源性模型的验证统计表明模型质量合理。c端结构域呈现αββαβ折叠，Arg325为α2-螺旋的倒数第二个n端残基。Arg325和Trp325的侧链都指向远离另一个单体的界面，而Arg325的ε-NH3+基团预测与Asp326和Asp295的β-COO-基团形成离子相互作用。对β2-α2 c末端环结构域的氨基酸比对显示，不同ZnT-8蛋白的325位存在多种中性氨基酸。我们验证的同源性模型预测，具有螺旋形成行为的氨基酸Arg325和Trp325，以及c -末端结构域α2-螺旋的倒数第二n端残基，都被三个细胞质β-链的平面表面所屏蔽，因此无法影响c -末端结构域的传感能力。此外，325位的氨基酸残基距离ZnT-8的对接和转运体部分太远，无法影响其局部蛋白质构象。这些数据表明，SLC30A8基因的遗传性R325W异常可能是耐受的，并导致足够的锌转移到胰岛细胞的正确位置，这与SLC30A8基因变异R325W在人群水平上对未来2型糖尿病的预测价值较低的观察结果一致。
We examined the effects of the R325W mutation on the three-dimensional (3D) structure of the β-cell-specific Zn2+ (zinc) transporter ZnT-8. A model of the C-terminal domain of the human ZnT-8 protein was generated by homology modeling based on the known crystal structure of the Escherichia coli (E. coli) zinc transporter YiiP at 3.8 Å resolution. The homodimer ZnT-8 protein structure exists as a Y-shaped architecture with Arg325 located at the ultimate bottom of this motif at approximately 13.5 Å from the transmembrane domain juncture. The C-terminal domain sequences of the human ZnT-8 protein and the E. coli zinc transporter YiiP share 12.3% identical and 39.5% homologous residues resulting in an overall homology of 51.8%. Validation statistics of the homology model showed a reasonable quality of the model. The C-terminal domain exhibited an αββαβ fold with Arg325 as the penultimate N-terminal residue of the α2-helix. The side chains of both Arg325 and Trp325 point away from the interface with the other monomer, whereas the ε-NH3+ group of Arg325 is predicted to form an ionic interaction with the β-COO- group of Asp326 as well as Asp295. An amino acid alignment of the β2-α2 C-terminal loop domain revealed a variety of neutral amino acids at position 325 of different ZnT-8 proteins. Our validated homology models predict that both Arg325 and Trp325, amino acids with a helix-forming behavior, and penultimate N-terminal residues in the α2-helix of the C-terminal domain, are shielded by the planar surface of the three cytoplasmic β-strands and hence unable to affect the sensing capacity of the C-terminal domain. Moreover, the amino acid residue at position 325 is too far removed from the docking and transporter parts of ZnT-8 to affect their local protein conformations. These data indicate that the inherited R325W abnormality in SLC30A8 may be tolerated and results in adequate zinc transfer to the correct sites in the pancreatic islet cells and are consistent with the observation that the SLC30A8 gene variant R325W has a low predicted value for future type 2 diabetes at population-based level.
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评估18种常见遗传变异的综合遗传变异对2型糖尿病风险的综合影响。
影响因子：
7.7
作者：
Lango H;UK Type 2 Diabetes Genetics Consortium;Palmer CN;Morris AD;Zeggini E;Hattersley AT;McCarthy MI;Frayling TM;Weedon MN
通讯作者：
Weedon MN
影响因子：
4.1
作者：
Peter, GJ;Davies, A;Taylor, PM
通讯作者：
Taylor, PM
影响因子：
7.7
作者：
Chimienti, F;Devergnas, S;Seve, M
通讯作者：
Seve, M
影响因子：
11.4
作者：
CHOTHIA, C;LESK, AM
通讯作者：
LESK, AM
影响因子：
4
作者：
Chimienti, Fabrice;Devergnas, Severine;Seve, Michel
通讯作者：
Seve, Michel