Cordat Emmanuelle, Reithmeier Reinhart A F
Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
Department of Biochemistry, 1 King's College Circle, University of Toronto, Toronto, Ontario, Canada.
Curr Top Membr. 2014;73:1-67. doi: 10.1016/B978-0-12-800223-0.00001-3.
The structure and function of the red cell anion exchanger 1 (AE1, Band 3, SLC4A1), the truncated kidney anion exchanger 1 (kAE1), and the other members of the SLC4 family of bicarbonate transporters are reviewed. Mutations in the AE1 gene cause human diseases like Southeast Asian ovalocytosis and hereditary spherocytosis in the red cell and distal renal tubular acidosis in the kidney. These mutations affect the folding, trafficking, and functional expression of these membrane glycoproteins. In the SLC26 family of anion transporters, mutations also cause trafficking defects and human disease. Membrane glycoproteins are cotranslationally N-glycosylated in the endoplasmic reticulum (ER) and when properly folded, traffic via the secretory pathway to their final destination such as the plasma membrane. Misfolded glycoproteins are retained in ER and are targeted for degradation by the proteasome following retrotranslocation and ubiquitinylation. ER chaperones, like membrane-bound calnexin, interact transiently with glycoproteins and are part of the quality control system that monitors the folding of glycoproteins during their biosynthesis. Recent results have indicated that it is possible to "correct" trafficking defects caused by some mutations in the SLC4 and 26 families through the use of small molecules that interfere with the interaction of glycoproteins with the components of the quality control system. This review summarizes the current knowledge on structure and function of anion transporters from the SLC4 and SLC26 families, and the effect of mutations on their trafficking and functional expression.
本文综述了红细胞阴离子交换蛋白1（AE1，带3蛋白，SLC4A1）、截短型肾阴离子交换蛋白1（kAE1）以及SLC4家族中其他碳酸氢盐转运蛋白的结构与功能。AE1基因突变会导致人类疾病，如红细胞中的东南亚椭圆形红细胞增多症和遗传性球形红细胞增多症，以及肾脏中的远端肾小管酸中毒。这些突变影响这些膜糖蛋白的折叠、运输和功能表达。在阴离子转运蛋白的SLC26家族中，突变也会导致运输缺陷和人类疾病。膜糖蛋白在内质网（ER）中进行共翻译N-糖基化，正确折叠后，通过分泌途径运输到其最终目的地，如质膜。错误折叠的糖蛋白会保留在内质网中，并在逆向转运和泛素化后被蛋白酶体靶向降解。内质网伴侣蛋白，如膜结合钙连蛋白，会与糖蛋白短暂相互作用，是在糖蛋白生物合成过程中监测其折叠的质量控制系统的一部分。最近的研究结果表明，通过使用小分子干扰糖蛋白与质量控制系统成分的相互作用，可以“纠正”由SLC4和26家族中某些突变引起的运输缺陷。本文综述了目前关于SLC4和SLC26家族阴离子转运蛋白的结构和功能的知识，以及突变对其运输和功能表达的影响。
