Cryo-EM structures of the human cation-chloride cotransporter KCC1

Science ◽  
2019 ◽  
Vol 366 (6464) ◽  
pp. 505-508 ◽  
Author(s):  
Si Liu ◽  
Shenghai Chang ◽  
Binming Han ◽  
Lingyi Xu ◽  
Mingfeng Zhang ◽  
...  
Keyword(s):  
Ion Transport ◽  
Potassium Chloride ◽  
Volume Regulation ◽  
Cell Volume Regulation ◽  
Aminobutyric Acid ◽  
Computational Studies ◽  
Transport Activity ◽  
Cryo Electron Microscopy ◽  
Cation Chloride Cotransporters ◽  
Functional Analyses

Cation-chloride cotransporters (CCCs) mediate the coupled, electroneutral symport of cations with chloride across the plasma membrane and are vital for cell volume regulation, salt reabsorption in the kidney, and γ-aminobutyric acid (GABA)–mediated modulation in neurons. Here we present cryo–electron microscopy (cryo-EM) structures of human potassium-chloride cotransporter KCC1 in potassium chloride or sodium chloride at 2.9- to 3.5-angstrom resolution. KCC1 exists as a dimer, with both extracellular and transmembrane domains involved in dimerization. The structural and functional analyses, along with computational studies, reveal one potassium site and two chloride sites in KCC1, which are all required for the ion transport activity. KCC1 adopts an inward-facing conformation, with the extracellular gate occluded. The KCC1 structures allow us to model a potential ion transport mechanism in KCCs and provide a blueprint for drug design.

scholarly journals Structures and an activation mechanism of human potassium-chloride cotransporters

2020 ◽  
Vol 6 (50) ◽  
pp. eabc5883 ◽  
Author(s):  
Yuan Xie ◽  
Shenghai Chang ◽  
Cheng Zhao ◽  
Feng Wang ◽  
Si Liu ◽  
...  
Keyword(s):  
Potassium Chloride ◽  
Volume Regulation ◽  
Transmembrane Domain ◽  
Cell Volume Regulation ◽  
Full Length ◽  
Aminobutyric Acid ◽  
Activation Mechanism ◽  
Inhibitory Peptide ◽  
Domain Swap ◽  
Functional Studies

Potassium-chloride cotransporters KCC1 to KCC4 mediate the coupled export of potassium and chloride across the plasma membrane and play important roles in cell volume regulation, auditory system function, and γ-aminobutyric acid (GABA) and glycine-mediated inhibitory neurotransmission. Here, we present 2.9- to 3.6-Å resolution structures of full-length human KCC2, KCC3, and KCC4. All three KCCs adopt a similar overall architecture, a domain-swap dimeric assembly, and an inward-facing conformation. The structural and functional studies reveal that one unexpected N-terminal peptide binds at the cytosolic facing cavity and locks KCC2 and KCC4 at an autoinhibition state. The C-terminal domain (CTD) directly interacts with the N-terminal inhibitory peptide, and the relative motions between the CTD and the transmembrane domain (TMD) suggest that CTD regulates KCCs’ activities by adjusting the autoinhibitory effect. These structures provide the first glimpse of full-length structures of KCCs and an autoinhibition mechanism among the amino acid–polyamine-organocation transporter superfamily.

scholarly journals The Important Role of Ion Transport System in Cervical Cancer

2021 ◽  
Vol 23 (1) ◽  
pp. 333
Author(s):  
Yih-Fung Chen ◽  
Meng-Ru Shen
Keyword(s):  
Cervical Cancer ◽  
Epithelial Cells ◽  
Ion Transport ◽  
Cell Volume ◽  
Volume Regulation ◽  
Gynecological Cancer ◽  
Cell Volume Regulation ◽  
Hpv Infection ◽  
Transport Processes ◽  
Transport Systems

Cervical cancer is a significant gynecological cancer and causes cancer-related deaths worldwide. Human papillomavirus (HPV) is implicated in the etiology of cervical malignancy. However, much evidence indicates that HPV infection is a necessary but not sufficient cause in cervical carcinogenesis. Therefore, the cellular pathophysiology of cervical cancer is worthy of study. This review summarizes the recent findings concerning the ion transport processes involved in cell volume regulation and intracellular Ca2+ homeostasis of epithelial cells and how these transport systems are themselves regulated by the tumor microenvironment. For cell volume regulation, we focused on the volume-sensitive Cl− channels and K+-Cl− cotransporter (KCC) family, important regulators for ionic and osmotic homeostasis of epithelial cells. Regarding intracellular Ca2+ homeostasis, the Ca2+ store sensor STIM molecules and plasma membrane Ca2+ channel Orai proteins, the predominant Ca2+ entry mechanism in epithelial cells, are discussed. Furthermore, we evaluate the potential of these membrane ion transport systems as diagnostic biomarkers and pharmacological interventions and highlight the challenges.

scholarly journals Role of the Cation-Chloride-Cotransporters in Cardiovascular Disease

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2293 ◽  
Author(s):  
Nur Farah Meor Azlan ◽  
Jinwei Zhang
Keyword(s):  
Cardiovascular Disease ◽  
Potassium Chloride ◽  
Genetic Disorders ◽  
Ion Homeostasis ◽  
Cell Volume Regulation ◽  
Renal Cells ◽  
Sodium Potassium ◽  
Physiological Processes ◽  
Cation Chloride Cotransporters

The SLC12 family of cation-chloride-cotransporters (CCCs) is comprised of potassium chloride cotransporters (KCCs), which mediate Cl− extrusion and sodium-potassium chloride cotransporters (N[K]CCs), which mediate Cl− loading. The CCCs play vital roles in cell volume regulation and ion homeostasis. The functions of CCCs influence a variety of physiological processes, many of which overlap with the pathophysiology of cardiovascular disease. Although not all of the cotransporters have been linked to Mendelian genetic disorders, recent studies have provided new insights into their functional role in vascular and renal cells in addition to their contribution to cardiovascular diseases. Particularly, an imbalance in potassium levels promotes the pathogenesis of atherosclerosis and disturbances in sodium homeostasis are one of the causes of hypertension. Recent findings suggest hypothalamic signaling as a key signaling pathway in the pathophysiology of hypertension. In this review, we summarize and discuss the role of CCCs in cardiovascular disease with particular emphasis on knowledge gained in recent years on NKCCs and KCCs.

scholarly journals The structural basis of function and regulation of neuronal cotransporters NKCC1 and KCC2

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Sensen Zhang ◽  
Jun Zhou ◽  
Yuebin Zhang ◽  
Tianya Liu ◽  
Perrine Friedel ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Computational Analysis ◽  
Neuronal Excitability ◽  
Functional Characterization ◽  
Structural Basis ◽  
Structural Studies ◽  
Coupled Transport ◽  
Transport Activity ◽  
Cryo Electron Microscopy ◽  
Cation Chloride Cotransporters

AbstractNKCC and KCC transporters mediate coupled transport of Na++K++Cl− and K++Cl− across the plasma membrane, thus regulating cell Cl− concentration and cell volume and playing critical roles in transepithelial salt and water transport and in neuronal excitability. The function of these transporters has been intensively studied, but a mechanistic understanding has awaited structural studies of the transporters. Here, we present the cryo-electron microscopy (cryo-EM) structures of the two neuronal cation-chloride cotransporters human NKCC1 (SLC12A2) and mouse KCC2 (SLC12A5), along with computational analysis and functional characterization. These structures highlight essential residues in ion transport and allow us to propose mechanisms by which phosphorylation regulates transport activity.

scholarly journals Molecular basis for regulation of human potassium chloride cotransporters

2020 ◽  
Author(s):  
Ximin Chi ◽  
Xiaorong Li ◽  
Yun Chen ◽  
Yuanyuan Zhang ◽  
Qiang Su ◽  
...  
Keyword(s):  
Potassium Chloride ◽  
System Development ◽  
Cell Volume Regulation ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Chloride Homeostasis ◽  
Terminal Loop ◽  
Transport Path ◽  
Regulation Mechanisms ◽  
Cation Chloride Cotransporters

AbstractThe Solute Carrier Family 12 (SLC12) encodes electroneutral cation-chloride cotransporters (CCCs) that are fundamental in cell volume regulation and chloride homeostasis. Dysfunction of CCCs engenders abnormality in renal function and neuro-system development. Here we presented structure of the full length human potassium-chloride co-transporter 2 (KCC2) and 3 (KCC3), the KCC3 mutants in phosphorylation mimic (P-mimic) and dephosphorylation mimic (DP-mimic) status, and KCC3 in complex with [(DihydroIndenyl)Oxy] Alkanoic acid (DIOA), a specific inhibitor of KCCs, at resolution of 2.7 Å - 3.6 Å. A small N-terminal loop is bound at the intracellular vestibule of the transport path, arresting the transporter in an auto-inhibition state. The C-terminal domain (CTD) of KCCs is structure-solved for the first time, revealing two conserved phosphorylation harboring segments (PHSs), which exhibit different conformation between P-mimic and DP-mimic mutants, explaining the inhibitory effect of phosphorylation. DIOA is located in between the two transmembrane domains, tightly bound to the loop between TM10 and TM11, locking the transporter in inward-facing conformation. Together, our study makes important steps in understanding the sophisticated regulation mechanisms of KCCs, with prospect for the specific drug development.

Signal Transduction and Cell Volume Regulation in Plant Leaflet Movements

Physiology ◽  
1996 ◽  
Vol 11 (3) ◽  
pp. 108-114 ◽  
Author(s):  
N Moran ◽  
YG Yueh ◽  
RC Crain
Keyword(s):  
Signal Transduction ◽  
Ion Channels ◽  
Ion Transport ◽  
Cell Volume ◽  
Volume Regulation ◽  
Biological Clock ◽  
Cell Volume Regulation ◽  
Volume Changes ◽  
Effect Of Light

Leaflet movements and underlying cell volume changes are visual indicators of ion transport in specialized cells of various plants. These cells are an attractive model to study regulation of plant ion transport. We focus on the effect of light, the biological clock, and mechanosensing on ion channels mediating cell volume regulation.

scholarly journals dl-β-Aminobutyric Acid–Induced Resistance of Potato Against Phytophthora infestans Requires Salicylic Acid but Not Oxylipins

2010 ◽  
Vol 23 (5) ◽  
pp. 585-592 ◽  
Author(s):  
Lennart Eschen-Lippold ◽  
Simone Altmann ◽  
Sabine Rosahl
Keyword(s):  
Salicylic Acid ◽  
Phytophthora Infestans ◽  
Induced Resistance ◽  
Crop Plants ◽  
Aminobutyric Acid ◽  
Systemic Resistance ◽  
Lipoxygenase Pathway ◽  
Promising Alternative ◽  
Functional Analyses ◽  
Late Blight Pathogen

Inducing systemic resistance responses in crop plants is a promising alternative way of disease management. To understand the underlying signaling events leading to induced resistance, functional analyses of plants defective in defined signaling pathway steps are required. We used potato, one of the economically most-important crop plants worldwide, to examine systemic resistance against the devastating late blight pathogen Phytophthora infestans, induced by treatment with dl-β-aminobutyric acid (BABA). Transgenic plants impaired in either the 9-lipoxygenase pathway, which produces defense-related compounds, or the 13-lipoxygenase pathway, which generates jasmonic acid–derived signals, expressed wild-type levels of BABA-induced resistance. Plants incapable of accumulating salicylic acid (SA), on the other hand, failed to mount this type of induced resistance. Consistently, treatment of these plants with the SA analog 2,6-dichloroisonicotinic acid restored BABA-induced resistance. Together, these results demonstrate the indispensability of a functional SA pathway for systemic resistance in potato induced by BABA.

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