Domain-interface dynamics of CFTR revealed by stabilizing nanobodies

Maud Sigoillot, Marie Overtus, Magdalena Grodecka, Daniel Scholl, Abel Garcia-Pino, Toon Laeremans, Lihua He, Els Pardon, Ellen Hildebrandt, Ina Urbatsch, Jan Steyaert, John R Riordan, Cedric Govaerts

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


The leading cause of cystic fibrosis (CF) is the deletion of phenylalanine 508 (F508del) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR). The mutation affects the thermodynamic stability of the domain and the integrity of the interface between NBD1 and the transmembrane domain leading to its clearance by the quality control system. Here, we develop nanobodies targeting NBD1 of human CFTR and demonstrate their ability to stabilize both isolated NBD1 and full-length protein. Crystal structures of NBD1-nanobody complexes provide an atomic description of the epitopes and reveal the molecular basis for stabilization. Furthermore, our data uncover a conformation of CFTR, involving detachment of NBD1 from the transmembrane domain, which contrast with the compact assembly observed in cryo-EM structures. This unexpected interface rearrangement is likely to have major relevance for CF pathogenesis but also for the normal function of CFTR and other ABC proteins.

Original languageEnglish
Article number2636
Number of pages12
JournalNature Communications
Issue number1
Publication statusPublished - 14 Jun 2019


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