Evidence map›Paper›PMID 34031912›Full record

ArticleThe EMBO journal2021

Phospho-regulation, nucleotide binding and ion access control in potassium-chloride cotransporters.

Gamma Chi, Rebecca Ebenhoch, Henry Man, Haiping Tang, Laurence E Tremblay, Gabriella Reggiano, Xingyu Qiu, Tina Bohstedt, Idlir Liko, Fernando G Almeida and 17 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The EMBO journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.

0numbers the graph read from it
0cells of the map it votes in
26citing papers in PubMed
2.4field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

26 citing papers in PubMed, 40 citations in OpenAlex.

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

27 authors at 4 institutions in 3 countries.

Gamma ChiNuffield Department of Medicine, Centre of Medicines Discovery, University of Oxford, Oxford, UK.
Rebecca EbenhochNuffield Department of Medicine, Centre of Medicines Discovery, University of Oxford, Oxford, UK.
Henry ManNuffield Department of Medicine, Centre of Medicines Discovery, University of Oxford, Oxford, UK.
Haiping TangPhysical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, UK.
Laurence E TremblayDepartment of Medicine, Nephrology Research Group, Faculty of Medicine, Laval University, Quebec City, QC, Canada.
Gabriella ReggianoDepartment of Biochemistry, University of Washington, Seattle, WA, USA.
Xingyu QiuPhysical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, UK.
Tina BohstedtNuffield Department of Medicine, Centre of Medicines Discovery, University of Oxford, Oxford, UK.
Idlir LikoOMass Therapeutics, Ltd., Oxford, UK.
Fernando G AlmeidaOMass Therapeutics, Ltd., Oxford, UK.
Alexandre P GarneauDepartment of Medicine, Nephrology Research Group, Faculty of Medicine, Laval University, Quebec City, QC, Canada.
Dong WangNuffield Department of Medicine, Centre of Medicines Discovery, University of Oxford, Oxford, UK.
Gavin McKinleyNuffield Department of Medicine, Centre of Medicines Discovery, University of Oxford, Oxford, UK.
Christophe P MoreauNuffield Department of Medicine, Centre of Medicines Discovery, University of Oxford, Oxford, UK.
Kiran D BountraOMass Therapeutics, Ltd., Oxford, UK.
Patrizia AbrusciNuffield Department of Medicine, Centre of Medicines Discovery, University of Oxford, Oxford, UK.
Shubhashish M M MukhopadhyayNuffield Department of Medicine, Centre of Medicines Discovery, University of Oxford, Oxford, UK.
Alejandra Fernandez-CidNuffield Department of Medicine, Centre of Medicines Discovery, University of Oxford, Oxford, UK.
Samira SlimaniDepartment of Medicine, Nephrology Research Group, Faculty of Medicine, Laval University, Quebec City, QC, Canada.
Julie L LavoieCardiometabolic Axis, School of Kinesiology and Physical Activity Sciences, University of Montréal, Montréal, QC, Canada.
Nicola A Burgess-BrownNuffield Department of Medicine, Centre of Medicines Discovery, University of Oxford, Oxford, UK.
Ben TehanOMass Therapeutics, Ltd., Oxford, UK.
Frank DiMaioDepartment of Biochemistry, University of Washington, Seattle, WA, USA.
Ali JazayeriOMass Therapeutics, Ltd., Oxford, UK.
Paul IsenringDepartment of Medicine, Nephrology Research Group, Faculty of Medicine, Laval University, Quebec City, QC, Canada.
Carol V RobinsonPhysical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, UK.
Katharina L DürrNuffield Department of Medicine, Centre of Medicines Discovery, University of Oxford, Oxford, UK.ORCID 0000-0002-3245-4088
University of Oxford · GBUniversité Laval · CAUniversity of Washington · USUniversité de Montréal · CA

Funding

Medical Research Council MC_PC_17136Medical Research Council MC_PC_17137Wellcome TrustWellcome Trust 060208/Z/00/ZWellcome Trust 093305/Z/10/Z
6 · The paper itself

Abstract

Potassium-coupled chloride transporters (KCCs) play crucial roles in regulating cell volume and intracellular chloride concentration. They are characteristically inhibited under isotonic conditions via phospho-regulatory sites located within the cytoplasmic termini. Decreased inhibitory phosphorylation in response to hypotonic cell swelling stimulates transport activity, and dysfunction of this regulatory process has been associated with various human diseases. Here, we present cryo-EM structures of human KCC3b and KCC1, revealing structural determinants for phospho-regulation in both N- and C-termini. We show that phospho-mimetic KCC3b is arrested in an inward-facing state in which intracellular ion access is blocked by extensive contacts with the N-terminus. In another mutant with increased isotonic transport activity, KCC1Δ19, this interdomain interaction is absent, likely due to a unique phospho-regulatory site in the KCC1 N-terminus. Furthermore, we map additional phosphorylation sites as well as a previously unknown ATP/ADP-binding pocket in the large C-terminal domain and show enhanced thermal stabilization of other CCCs by adenine nucleotides. These findings provide fundamentally new insights into the complex regulation of KCCs and may unlock innovative strategies for drug development.

Indexed as

AnimalsCell LineCell SizeChloridesHumansK Cl- CotransportersNucleotidesPhosphorylationPotassiumSf9 CellsSignal TransductionSymportersChloridesK Cl- CotransportersNucleotidesPotassiumSymportersHDX-MSnucleotide bindingphospho-regulationpotassium-chloride co-transportsolute carrier

Identifiers

PMID34031912
PMCPMC8280820
OpenAlexW3164769147

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.