Membrane-traversing mechanism of thyroid hormone transport by monocarboxylate transporter 8
Membrane-traversing mechanism of thyroid hormone transport by monocarboxylate transporter 8
复制标题
DOI：
10.1007/s00018-017-2461-9
复制
发表时间：
2017-06-01
影响因子：
8
通讯作者：
Krause, Gerd
中科院分区：
文献类型：
--
作者：
Protze, Jonas;Braun, Doreen;Krause, Gerd
单羧酸转运蛋白8（MCT 8）介导甲状腺激素（TH）在许多细胞类型中跨质膜转运。为了更好地理解其机制，我们基于细胞内开放（PDB ID：4aj 4）和细胞外部分封闭（PDB ID：4gby）构象中的糖转运蛋白XylE以及完全细胞外开放构象中的FucP（PDB ID：3 o 7 q）和GLUT 3（PDB ID：4 zwc）产生了三种新的MCT 8同源模型。来自两侧的T-3对接研究揭示了与His 192、His 415、Arg 445和Asp 498的相互作用，如先前所鉴定的。选定的突变揭示了进一步的转运敏感的位置，主要是在不连续的跨膜螺旋TMH 7和10。Lys 418可能参与中和TH底物的电荷，因为它可以被带电荷的氨基酸取代，但不能被不带电荷的氨基酸取代。假设Thr 503的侧链稳定在TMH 10处的螺旋断裂，其在运输循环期间经历显著的局部移位。因此，T503 V突变影响了转运。研究了排列在转运通道上的芳香族Tyr 419、极性Ser 313和Ser 314以及带电的Glu 422和Glu 423。基于相关的糖转运蛋白，我们提出了一个交替的访问机制，涉及一系列的氨基酸位置以前和新确定的关键运输的MCT 8。
Monocarboxylate transporter 8 (MCT8) mediates thyroid hormone (TH) transport across the plasma membrane in many cell types. In order to better understand its mechanism, we have generated three new MCT8 homology models based on sugar transporters XylE in the intracellular opened (PDB ID: 4aj4) and the extracellular partly occluded (PDB ID: 4gby) conformations as well as FucP (PDB ID: 3o7q) and GLUT3 (PDB ID: 4zwc) in the fully extracellular opened conformation. T-3-docking studies from both sides revealed interactions with His192, His415, Arg445 and Asp498 as previously identified. Selected mutations revealed further transport-sensitive positions mainly at the discontinuous transmembrane helices TMH7 and 10. Lys418 is potentially involved in neutralising the charge of the TH substrate because it can be replaced by charged, but not by uncharged, amino acids. The side chain of Thr503 was hypothesised to stabilise a helix break at TMH10 that undergoes a prominent local shift during the transport cycle. A T503V mutation accordingly affected transport. The aromatic Tyr419, the polar Ser313 and Ser314 as well as the charged Glu422 and Glu423 lining the transport channel have been studied. Based on related sugar transporters, we suggest an alternating access mechanism for MCT8 involving a series of amino acid positions previously and newly identified as critical for transport.