Mammalian SLC26 proteins are membrane-based anion transporters that belong to the large SLC26/SulP family, and many of their variants are associated with hereditary diseases. Recent structural studies revealed a strikingly similar homodimeric molecular architecture for several SLC26 members, implying a shared molecular principle. Now a new question emerges as to how these structurally similar proteins execute diverse physiological functions. In this study, we sought to identify the common distinct molecular mechanism among the SLC26 proteins using both naturally occurring and artificial missense changes introduced to SLC26A4, SLC26A5, and SLC26A9. We found: (i) the basic residue at the anion binding site is essential for both anion antiport of SLC26A4 and motor functions of SLC26A5, and its conversion to a nonpolar residue is crucial but not sufficient for the fast uncoupled anion transport in SLC26A9; (ii) the conserved polar residues in the N- and C-terminal cytosolic domains are likely involved in dynamic hydrogen-bonding networks and are essential for anion antiport of SLC26A4 but not for motor (SLC26A5) and uncoupled anion transport (SLC26A9) functions; (iii) the hydrophobic interaction between each protomer’s last transmembrane helices, TM14, is not of functional significance in SLC26A9 but crucial for the functions of SLC26A4 and SLC26A5, likely contributing to optimally orient the axis of the relative movements of the core domain with respect to the gate domains within the cell membrane. These findings advance our understanding of the molecular mechanisms underlying the diverse physiological roles of the SLC26 family of proteins.

中文翻译：

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SLC26 蛋白家族不同功能的分子原理


哺乳动物 SLC26 蛋白是基于膜的阴离子转运蛋白，属于 SLC26/SulP 大家族，其许多变体与遗传性疾病有关。最近的结构研究揭示了几个 SLC26 成员具有惊人相似的同二聚体分子结构，这意味着共同的分子原理。现在出现了一个新问题：这些结构相似的蛋白质如何执行不同的生理功能。在这项研究中，我们试图利用引入 SLC26A4、SLC26A5 和 SLC26A9 的自然发生和人工错义变化来鉴定 SLC26 蛋白之间共同的独特分子机制。我们发现：（i）阴离子结合位点的碱性残基对于SLC26A4的阴离子反向转运和SLC26A5的运动功能都是必需的，并且其向非极性残基的转化是至关重要的，但对于SLC26A9中的快速解偶联阴离子转运来说还不够； (ii) N 端和 C 端胞质结构域中的保守极性残基可能参与动态氢键网络，并且对于 SLC26A4 的阴离子反向转运至关重要，但对于运动 (SLC26A5) 和非偶联阴离子转运 (SLC26A9) 功能则不然； (iii) 每个原体最后的跨膜螺旋 TM14 之间的疏水相互作用在 SLC26A9 中不具有功能意义，但对于 SLC26A4 和 SLC26A5 的功能至关重要，可能有助于优化核心结构域相对运动轴的方向细胞膜内的门域。这些发现增进了我们对 SLC26 蛋白家族不同生理作用的分子机制的理解。