Acidic residues of extracellular loop 3 of the Na+/H+ exchanger type 1 are important in cation transport

Li, Xiuju; Quan, Sicheng; Corsiatto, Thomas; Fliegel, Larry

doi:10.1007/s11010-020-03707-9

Cited by 5 publications

(3 citation statements)

References 36 publications

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“…The NHE9 monomer consists of 13 TMs with an extracellular N‐terminus and intracellular C‐terminus (Fig 2A and Appendix Fig S4A). The NHE9 structure is therefore more similar to the bacterial homologue structures with 13 TMs and a 6‐TM topology inverted repeat, namely NapA (Lee et al , 2013), Mj NhaP (Paulino et al , 2014) and Pa NhaP (Wöhlert et al , 2014), rather than the more commonly used NHE models that, like NhaA, have 12 TMs and a 5‐TM topology inverted repeat (Hunte et al , 2005; Landau et al , 2007; Kondapalli et al , 2013; Hendus‐Altenburger et al , 2014; Pedersen & Counillon, 2019; Li et al , 2020; Appendix Fig S4B). The expansion of the inverted‐topology repeats establishes a dimerization interface that in NHE9, and the bacterial antiporters with 13 TMs, is formed predominantly by tight interactions between TM1 on one monomer and TM8 on the other, burying a total surface area of ~ 1,700 to 2,000 Å 2 (Fig EV4A).…”

Section: Resultsmentioning

confidence: 99%

Structure and elevator mechanism of the mammalian sodium/proton exchanger NHE9

et al. 2020

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Na+/H+ exchangers (NHEs) are ancient membrane‐bound nanomachines that work to regulate intracellular pH, sodium levels and cell volume. NHE activities contribute to the control of the cell cycle, cell proliferation, cell migration and vesicle trafficking. NHE dysfunction has been linked to many diseases, and they are targets of pharmaceutical drugs. Despite their fundamental importance to cell homeostasis and human physiology, structural information for the mammalian NHE was lacking. Here, we report the cryogenic electron microscopy structure of NHE isoform 9 (SLC9A9) from Equus caballus at 3.2 Å resolution, an endosomal isoform highly expressed in the brain and associated with autism spectrum (ASD) and attention deficit hyperactivity (ADHD) disorders. Despite low sequence identity, the NHE9 architecture and ion‐binding site are remarkably similar to distantly related bacterial Na+/H+ antiporters with 13 transmembrane segments. Collectively, we reveal the conserved architecture of the NHE ion‐binding site, their elevator‐like structural transitions, the functional implications of autism disease mutations and the role of phosphoinositide lipids to promote homodimerization that, together, have important physiological ramifications.

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Section: Resultsmentioning

confidence: 99%

Structure and elevator mechanism of the mammalian sodium/proton exchanger NHE9

et al. 2020

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“…NHE7, a unique protein member of the NHE family, dynamically shuttles across the Golgi network between endosomes and the plasma membrane to regulate the intraluminal pH in these organelles. NHE7 overexpression in MDA-MB-231 breast cancer cells enhances the tumor cell coverage area, cell-cell adhesion and cell invasion, which is independent of tumor growth and tumor sphericity (64), according to the first report (63) indicating that NHE participates in tumor regulation at the organelle level. In studies on antitumor therapy, it was confirmed that the inhibition of NHE1 expression and activity may act synergistically with paclitaxel to induce cell apoptosis, and it has been confirmed that PKA and p38 are upstream regulatory points of NHE1 in the induction of paclitaxel-dependent apoptosis.…”

Section: Nhe1 and Breast Cancermentioning

confidence: 99%

“…Among the signaling pathways involved in cancer cell invasion, PRL-mediated activation of AKT and ERK1/2 activates p90RSK, which leads to the phosphorylation of NHE1 Ser703, thereby increasing NHE1 activity, including NHE1-dependent cell migration (62). As a pHi regulatory protein, a previous study examined the role of negatively charged amino acids of extracellular loop 3 (EL3) in the activity of the NHE protein, and demonstrated that amino acids E217 and D226 form part of a negatively charged coordination sphere, which facilitates cation transport in the NHE1 protein (63). NHE7, a unique protein member of the NHE family, dynamically shuttles across the Golgi network between endosomes and the plasma membrane to regulate the intraluminal pH in these organelles.…”

Section: Nhe1 and Breast Cancermentioning

confidence: 99%

Advances in research on the regulatory mechanism of NHE1 in tumors (Review)

Lou

Jin

et al. 2021

Oncol Lett

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Tumors pose a major threat to human health and present with difficulties that modern medicine has yet to overcome. It has been demonstrated that the acid-base balance of the tumor microenvironment is closely associated with the dynamic balance in the human body and that it regulates several processes, such as cell proliferation and differentiation, intracellular enzyme activity, and cytoskeletal assembly and depolymerization. It has been well established that the regulation of intra-and extracellular pH depends on a series of functional ion transporters and hydrogen ion channels, such as the Na + /H + exchanger (NHE) protein and thee Cl/HCO 3-exchange protein, among which the NHE1 member of the NHE family has been attracting increasing attention in recent years, particularly in studies on the correlation between pH regulation and tumors. NHE1 is a housekeeping gene encoding a protein that is widely expressed on the surface of all plasma membranes. Due to its functional domain, which determines the pHi at its N-terminus and C-terminus, NHE1 is involved in the regulation of the cellular pH microenvironment. It has been reported in the literature that NHE1 can regulate cell volume, participate in the transmembrane transport of intracellular and extracellular ions, affect cell proliferation and apoptosis, and regulate cell behavior and cell cycle progression; however, research on the role of NHE1 in tumorigenesis and tumor development in various systems is at its early stages. The aim of the present study was to review the current research on the correlation between the NHE family proteins and various systemic tumors, in order to indicate a new direction for antitumor drug development with the pH microenvironment as the target.

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