8gv8 | pdb_00008gv8
The cryo-EM structure of hAE2 with DIDS
Structural highlights
DiseaseB3A2_HUMAN The disease may be caused by variants affecting the gene represented in this entry. FunctionB3A2_HUMAN Sodium-independent anion exchanger which mediates the electroneutral exchange of chloride for bicarbonate ions across the cell membrane (PubMed:15184086, PubMed:34668226). Plays an important role in osteoclast differentiation and function (PubMed:34668226). Regulates bone resorption and calpain-dependent actin cytoskeleton organization in osteoclasts via anion exchange-dependent control of pH (By similarity). Essential for intracellular pH regulation in CD8(+) T-cells upon CD3 stimulation, modulating CD8(+) T-cell responses (By similarity).[UniProtKB:P13808][1] [2] Publication Abstract from PubMedThe cell maintains its intracellular pH in a narrow physiological range and disrupting the pH-homeostasis could cause dysfunctional metabolic states. Anion exchanger 2 (AE2) works at high cellular pH to catalyze the exchange between the intracellular HCO(3)(-) and extracellular Cl(-), thereby maintaining the pH-homeostasis. Here, we determine the cryo-EM structures of human AE2 in five major operating states and one transitional hybrid state. Among those states, the AE2 shows the inward-facing, outward-facing, and intermediate conformations, as well as the substrate-binding pockets at two sides of the cell membrane. Furthermore, critical structural features were identified showing an interlock mechanism for interactions among the cytoplasmic N-terminal domain and the transmembrane domain and the self-inhibitory effect of the C-terminal loop. The structural and cell-based functional assay collectively demonstrate the dynamic process of the anion exchange across membranes and provide the structural basis for the pH-sensitive pH-rebalancing activity of AE2. The structural basis of the pH-homeostasis mediated by the Cl(-)/HCO(3)(-) exchanger, AE2.,Zhang Q, Jian L, Yao D, Rao B, Xia Y, Hu K, Li S, Shen Y, Cao M, Qin A, Zhao J, Cao Y Nat Commun. 2023 Mar 31;14(1):1812. doi: 10.1038/s41467-023-37557-y. PMID:37002221[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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