BIBLIOS

Document type
Journal articles

Document subtype
Full paper

Title
Full Rescue of F508del-CFTR Processing and Function by CFTR Modulators Can Be Achieved by Removal of Two Regulatory Regions

Participants in the publication
Inna Uliyakina (Author)
Hugo M. Botelho (Author)
BioISI
Ana C. da Paula (Author)
BioISI - Biosystems & Integrative Sciences Institute
Sara Afonso (Author)
Miguel J. Lobo (Author)
BioISI - Biosystems & Integrative Sciences Institute
Verónica Felício (Author)
BioISI - Biosystems & Integrative Sciences Institute
Carlos M. Farinha (Author)
Dep. Química e Bioquímica
BioISI
Margarida D. Amaral (Author)
Dep. Química e Bioquímica
BioISI

Summary
Cystic Fibrosis (CF) is caused by mutations in the CF Transmembrane conductance Regulator (CFTR), the only ATP-binding cassette (ABC) transporter functioning as a channel. Unique to CFTR is a regulatory domain which includes a highly conformationally dynamic region—the regulatory extension (RE). The first nucleotide-binding domain of CFTR contains another dynamic region—regulatory insertion (RI). Removal of RI rescues the trafficking defect of CFTR with F508del, the most common CF-causing mutation. Here we aimed to assess the impact of RE removal (with/without RI or genetic revertants) on F508del-CFTR trafficking and how CFTR modulator drugs VX-809/lumacaftor and VX-770/ivacaftor rescue these variants. We generated cell lines expressing ΔRE and ΔRI CFTR (with/without genetic revertants) and assessed CFTR expression, stability, plasma membrane levels, and channel activity. Our data demonstrated that ΔRI significantly enhanced rescue of F508del-CFTR by VX-809. While the presence of the RI seems to be precluding full rescue of F508del-CFTR processing by VX-809, this region appears essential to rescue its function by VX-770, suggesting some contradictory role in rescue of F508del-CFTR by these two modulators. This negative impact of RI removal on VX-770-stimulated currents on F508del-CFTR can be compensated by deletion of the RE which also leads to the stabilization of this mutant. Despite both regions being conformationally dynamic, RI precludes F508del-CFTR processing while RE affects mostly its stability and channel opening.\\n\\n


Where published
International Journal of Molecular Sciences

Publication Identifiers
ISSN - 1422-0067

Publisher
MDPI AG



Document Identifiers
DOI - https://doi.org/10.3390/ijms21124524
URL - http://dx.doi.org/10.3390/ijms21124524

Rankings
SCIMAGO Q1 (2016) - 1.235 - Medicine (miscellaneous)
SCIMAGO Q1 (2017) - 1.26 - Medicine (miscellaneous)
SCIMAGO Q1 (2018) - 1.312 - Medicine (miscellaneous)
SCOPUS Q1 (2017) - 1.26 - Molecular Biology
SCIMAGO Q1 (2019) - 1.317 - Medicine (miscellaneous)
Web Of Science Q1 (2020) - 5.924 - BIOCHEMISTRY & MOLECULAR BIOLOGY - SCIE
SCIMAGO Q1 (2020) - 1.455 - Computer Science Applications
SCIMAGO Q1 (2020) - 1.455 - Medicine (miscellaneous)
SCOPUS Q1 (2020) - 6 - Computer Science Applications

Keywords
ABC transporters drug action regulatory extension regulatory insertion mechanism of action