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 and Cedric Govaerts ()
Additional contact information
Maud Sigoillot: SFMB, Université Libre de Bruxelles (ULB)
Marie Overtus: SFMB, Université Libre de Bruxelles (ULB)
Magdalena Grodecka: SFMB, Université Libre de Bruxelles (ULB)
Daniel Scholl: SFMB, Université Libre de Bruxelles (ULB)
Abel Garcia-Pino: Laboratoire de Microbiologie Moléculaire et Cellulaire, ULB CP300, rue des Professeurs Jeener et Brachet 12
Toon Laeremans: Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Pleinlaan 2
Lihua He: University of North Carolina-Chapel Hill
Els Pardon: Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Pleinlaan 2
Ellen Hildebrandt: Texas Tech University Health Sciences Center
Ina Urbatsch: Texas Tech University Health Sciences Center
Jan Steyaert: Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Pleinlaan 2
John R. Riordan: University of North Carolina-Chapel Hill
Cedric Govaerts: SFMB, Université Libre de Bruxelles (ULB)

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10714-y

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