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Molecular dynamics and functional characterization of I37R-CFTR lasso mutation provide insights into channel gating activity.
Wong, Sharon L; Awatade, Nikhil T; Astore, Miro A; Allan, Katelin M; Carnell, Michael J; Slapetova, Iveta; Chen, Po-Chia; Capraro, Alexander; Fawcett, Laura K; Whan, Renee M; Griffith, Renate; Ooi, Chee Y; Kuyucak, Serdar; Jaffe, Adam; Waters, Shafagh A.
Afiliación
  • Wong SL; School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia.
  • Awatade NT; Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia.
  • Astore MA; School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia.
  • Allan KM; Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia.
  • Carnell MJ; School of Physics, University of Sydney, Sydney, Australia.
  • Slapetova I; School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia.
  • Chen PC; Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia.
  • Capraro A; Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, Australia.
  • Fawcett LK; Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, Australia.
  • Whan RM; School of Physics, University of Sydney, Sydney, Australia.
  • Griffith R; School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia.
  • Ooi CY; Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia.
  • Kuyucak S; School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia.
  • Jaffe A; Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia.
  • Waters SA; Department of Respiratory Medicine, Sydney Children's Hospital, Randwick, Australia.
iScience ; 25(1): 103710, 2022 Jan 21.
Article en En | MEDLINE | ID: mdl-35072004
Characterization of I37R, a mutation located in the lasso motif of the CFTR chloride channel, was conducted by theratyping several CFTR modulators from both potentiator and corrector classes. Intestinal current measurements in rectal biopsies, forskolin-induced swelling (FIS) in intestinal organoids, and short circuit current measurements in organoid-derived monolayers from an individual with I37R/F508del CFTR genotype demonstrated that the I37R-CFTR results in a residual function defect amenable to treatment with potentiators and type III, but not type I, correctors. Molecular dynamics of I37R using an extended model of the phosphorylated, ATP-bound human CFTR identified an altered lasso motif conformation which results in an unfavorable strengthening of the interactions between the lasso motif, the regulatory (R) domain, and the transmembrane domain 2 (TMD2). Structural and functional characterization of the I37R-CFTR mutation increases understanding of CFTR channel regulation and provides a potential pathway to expand drug access to CF patients with ultra-rare genotypes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: IScience Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: IScience Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos