Direct Interaction with Filamins Modulates the Stability and Plasma Membrane Expression of Cftr.
From: Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
The Journal of clinical investigation
- Publish Date: Feb 2007
- ISSN: 0021-9738
- Volume: 117
- Issue: 2
- Pages: 364-74
- Medium: Print
- Language: English
- Citation (JAMA): Thelin William R, Chen Yun, Gentzsch Martina, et al. Direct Interaction with Filamins Modulates the Stability and Plasma Membrane Expression of Cftr.. J. Clin. Invest. Feb 2007;117:364-74
Abstract
The role of the cystic fibrosis transmembrane conductance regulator (CFTR) as a cAMP-dependent chloride channel on the apical membrane of epithelia is well established. However, the processes by which CFTR is regulated on the cell surface are not clear. Here we report the identification of a protein-protein interaction between CFTR and the cytoskeletal filamin proteins. Using proteomic approaches, we identified filamins as proteins that associate with the extreme CFTR N terminus. Furthermore, we identified a disease-causing missense mutation in CFTR, serine 13 to phenylalanine (S13F), which disrupted this interaction. In cells, filamins tethered plasma membrane CFTR to the underlying actin network. This interaction stabilized CFTR at the cell surface and regulated the plasma membrane dynamics and confinement of the channel. In the absence of filamin binding, CFTR was internalized from the cell surface, where it prematurely accumulated in lysosomes and was ultimately degraded. Our data demonstrate what we believe to be a previously unrecognized role for the CFTR N terminus in the regulation of the plasma membrane stability and metabolic stability of CFTR. In addition, we elucidate the molecular defect associated with the S13F mutation.
Mesh Headings (Keywords): Amino Acid Sequence, Amino Acid Substitution, Animals, Binding Sites, Cell Line, Cell Membrane, Contractile Proteins, Cricetinae, Cystic Fibrosis Transmembrane Conductance Regulator, Drug Stability, Hela Cells, Humans, Kinetics, Microfilament Proteins, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Protein Binding, Protein Conformation, Proteomics, Recombinant Proteins, Sequence Homology, Amino Acid
Check for Full Text / PubMed Unique Identifier (PMID): 17235394
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.