Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL.
Department of Cell Physiology and Molecular Biophysics, Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX.
J Gen Physiol. 2021 Apr 5;153(4). doi: 10.1085/jgp.202012633.
The sodium/potassium-ATPase (NKA) is the enzyme that establishes gradients of sodium and potassium across the plasma membrane. NKA activity is tightly regulated for different physiological contexts through interactions with single-span transmembrane peptides, the FXYD proteins. This diverse family of regulators has in common a domain containing a Phe-X-Tyr-Asp (FXYD) motif, two conserved glycines, and one serine residue. In humans, there are seven tissue-specific FXYD proteins that differentially modulate NKA kinetics as appropriate for each system, providing dynamic responsiveness to changing physiological conditions. Our understanding of how FXYD proteins contribute to homeostasis has benefitted from recent advances described in this review: biochemical and biophysical studies have provided insight into regulatory mechanisms, genetic models have uncovered remarkable complexity of FXYD function in integrated physiological systems, new posttranslational modifications have been identified, high-resolution structural studies have revealed new details of the regulatory interaction with NKA, and new clinical correlations have been uncovered. In this review, we address the structural determinants of diverse FXYD functions and the special roles of FXYDs in various physiological systems. We also discuss the possible roles of FXYDs in protein trafficking and regulation of non-NKA targets.
钠/钾-ATP 酶（NKA）是一种在质膜两侧建立钠离子和钾离子梯度的酶。NKA 活性通过与单跨跨膜肽（FXYD 蛋白）的相互作用在不同的生理环境中受到严格调节。这个多样化的调节因子家族有一个共同的特征，即包含一个苯丙氨酸-丝氨酸-酪氨酸-天冬氨酸（FXYD）基序、两个保守的甘氨酸和一个丝氨酸残基。在人类中，有七种组织特异性的 FXYD 蛋白，它们根据每个系统的需要，对 NKA 动力学进行不同的调节，为不断变化的生理条件提供动态响应。我们对 FXYD 蛋白如何有助于维持体内平衡的理解得益于本综述中描述的最新进展：生化和生物物理研究提供了对调节机制的深入了解，遗传模型揭示了 FXYD 功能在综合生理系统中的惊人复杂性，新的翻译后修饰已被确定，高分辨率结构研究揭示了与 NKA 调节相互作用的新细节，新的临床相关性也被发现。在本综述中，我们探讨了 FXYD 多种功能的结构决定因素以及它们在各种生理系统中的特殊作用。我们还讨论了 FXYD 在蛋白质运输和非 NKA 靶标调节中的可能作用。
