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TitlePhospho-regulation, nucleotide binding and ion access control in potassium-chloride cotransporters.
Journal, issue, pagesEMBO J, Vol. 40, Issue 14, Page e107294, Year 2021
Publish dateJul 15, 2021
AuthorsGamma Chi / Rebecca Ebenhoch / Henry Man / Haiping Tang / Laurence E Tremblay / Gabriella Reggiano / Xingyu Qiu / Tina Bohstedt / Idlir Liko / Fernando G Almeida / Alexandre P Garneau / Dong Wang / Gavin McKinley / Christophe P Moreau / Kiran D Bountra / Patrizia Abrusci / Shubhashish M M Mukhopadhyay / Alejandra Fernandez-Cid / Samira Slimani / Julie L Lavoie / Nicola A Burgess-Brown / Ben Tehan / Frank DiMaio / Ali Jazayeri / Paul Isenring / Carol V Robinson / Katharina L Dürr /
PubMed AbstractPotassium-coupled chloride transporters (KCCs) play crucial roles in regulating cell volume and intracellular chloride concentration. They are characteristically inhibited under isotonic conditions ...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.
External linksEMBO J / PubMed:34031912 / PubMed Central
MethodsEM (single particle)
Resolution3.12 - 4.47 Å
Structure data

10704

6y5v

EMDB-10704, PDB-6y5v:
Structure of Human Potassium Chloride Transporter KCC3b (S45D/T940D/T997D) in KCl
Method: EM (single particle) / Resolution: 4.08 Å

11799

7ain

EMDB-11799, PDB-7ain:
Structure of Human Potassium Chloride Transporter KCC3 S45D/T940D/T997D in NaCl (Reference Map)
Method: EM (single particle) / Resolution: 3.2 Å

11800

7aio

EMDB-11800, PDB-7aio:
Structure of Human Potassium Chloride Transporter KCC3 S45D/T940D/T997D in NaCl (Subclass)
Method: EM (single particle) / Resolution: 3.31 Å

11801

7aip

EMDB-11801, PDB-7aip:
Structure of Human Potassium Chloride Transporter KCC1 in NaCl (Reference Map)
Method: EM (single particle) / Resolution: 3.12 Å

11802

7aiq

EMDB-11802, PDB-7aiq:
Structure of Human Potassium Chloride Transporter KCC1 in NaCl (Subclass 1)
Method: EM (single particle) / Resolution: 3.72 Å

11803

7air

EMDB-11803, PDB-7air:
Structure of Human Potassium Chloride Transporter KCC1 in NaCl (Subclass 2)
Method: EM (single particle) / Resolution: 3.66 Å

EMDB-11804:
Structure of Wild-Type Human Potassium Chloride Transporter KCC3 in NaCl (LMNG/CHS)
Method: EM (single particle) / Resolution: 4.02 Å

EMDB-11805:
Structure of Wild-type Human Potassium Chloride Transporter KCC3 in NaCl (MSP E3D1)
Method: EM (single particle) / Resolution: 4.47 Å

12311

7ngb

EMDB-12311, PDB-7ngb:
Structure of Wild-Type Human Potassium Chloride Transporter KCC3 in NaCl (LMNG/CHS)
Method: EM (single particle) / Resolution: 3.64 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Dimer / transporter / potassium chloride / KCC3 / SLC12A6 / APC / Structural Genomics / Structural Genomics Consortium / SGC / TRANSPORT PROTEIN / CCC / human membrane protein / homodimer / KCC / potassium-chloride coupled transporter / nucleotide-binding / KCC1

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