Molecular Structure of the Human CFTR Ion Channel

Liu, F; Zhang, Z; Csanády, L [Csanády, László (Biokémia), szerző] MTA-SE Lendület Ioncsatorna Kutatócsoport (SE / AOK / I / BMBI / BT); Gadsby, DC; Chen, J ✉

Angol nyelvű Szakcikk (Folyóiratcikk) Tudományos
Megjelent: CELL 0092-8674 1097-4172 169 (1) pp. 85-95.e8 2017
  • SJR Scopus - Biochemistry, Genetics and Molecular Biology (miscellaneous): D1
Azonosítók
Szakterületek:
  • Biofizika (pl. transzportmechanizmusok, bioenergetika, fluoreszcencia)
  • Enzimológia
  • Molekuláris biofizika
  • Szerkezetbiológia (kristallográfia és elektronmikroszkópia)
The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter that uniquely functions as an ion channel. Here, we present a 3.9 Å structure of dephosphorylated human CFTR without nucleotides, determined by electron cryomicroscopy (cryo-EM). Close resemblance of this human CFTR structure to zebrafish CFTR under identical conditions reinforces its relevance for understanding CFTR function. The human CFTR structure reveals a previously unresolved helix belonging to the R domain docked inside the intracellular vestibule, precluding channel opening. By analyzing the sigmoid time course of CFTR current activation, we propose that PKA phosphorylation of the R domain is enabled by its infrequent spontaneous disengagement, which also explains residual ATPase and gating activity of dephosphorylated CFTR. From comparison with MRP1, a feature distinguishing CFTR from all other ABC transporters is the helix-loop transition in transmembrane helix 8, which likely forms the structural basis for CFTR's channel function. © 2017 Elsevier Inc.
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2024-07-14 18:03