Molecular structure of the human CFTR ion channel

• Fangyu Liu ^[1] ; Zhe Zhang ^[1] ; László Csanády ^[2]
  1. [1] Rockefeller University

     Rockefeller University

     Estados Unidos

     
  2. [2] Semmelweis University

     Semmelweis University

     Hungría

     
• Localización: Cell, ISSN 0092-8674, Vol. 169, Nº. 1, 2017, págs. 85-95
• Idioma: inglés
• Texto completo no disponible (Saber más ...)
• Resumen

  • 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.