PDF(Pubmed)
Abstract：
Anion exchanger 3 (AE3) is pivotal in regulating intracellular pH across excitable tissues, yet its structural intricacies and functional dynamics remain underexplored compared to other anion exchangers. This study unveils the structural insights into human AE3, including the cryo-electron microscopy structures for AE3 transmembrane domains (TMD) and a chimera combining AE3 N-terminal domain (NTD) with AE2 TMD (hAE3NTD2TMD). Our analyzes reveal a substrate binding site, an NTD-TMD interlock mechanism, and a preference for an outward-facing conformation. Unlike AE2, which has more robust acid-loading capabilities, AE3\'s structure, including a less stable inward-facing conformation due to missing key NTD-TMD interactions, contributes to its moderated pH-modulating activity and increased sensitivity to the inhibitor DIDS. These structural differences underline AE3\'s distinct functional roles in specific tissues and underscore the complex interplay between structural dynamics and functional specificity within the anion exchanger family, enhancing our understanding of the physiological and pathological roles of the anion exchanger family.
摘要：
阴离子交换剂3（AE3）在调节整个兴奋组织的细胞内pH中起着关键作用，然而，与其他阴离子交换剂相比，其结构复杂性和功能动力学仍未得到充分探索。这项研究揭示了人类AE3的结构见解，包括AE3跨膜结构域（TMD）的低温电子显微镜结构以及将AE3N末端结构域（NTD）与AE2TMD（hAE3NTD2TMD）结合的嵌合体。我们的分析揭示了一个底物结合位点，NTD-TMD联锁机构，以及对面向外的构象的偏好。与AE2不同，AE2具有更强大的酸负载能力，AE3的结构，包括由于缺少关键的NTD-TMD相互作用而导致的不太稳定的面向内的构象，有助于其适度的pH调节活性和增加对抑制剂DIDS的敏感性。这些结构差异强调了AE3在特定组织中的独特功能作用，并强调了阴离子交换家族中结构动力学和功能特异性之间的复杂相互作用。增强我们对阴离子交换家族的生理和病理作用的理解。
