A functional R domain from cystic fibrosis transmembrane conductance regulator is predominantly unstructured in solution

Lynda S Ostedgaard; Olafur Baldursson; Daniel W Vermeer; Michael J Welsh; Andrew D Robertson

doi:10.1073/pnas.100588797

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A functional R domain from cystic fibrosis transmembrane conductance regulator is predominantly unstructured in solution

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A functional R domain from cystic fibrosis transmembrane conductance regulator is predominantly unstructured in solution

Lynda S Ostedgaard, Olafur Baldursson, Daniel W Vermeer, Michael J Welsh and Andrew D Robertson

Proceedings of the National Academy of Sciences - PNAS, Vol.97(10), pp.5657-5662

05/09/2000

DOI: 10.1073/pnas.100588797

PMCID: PMC25884

PMID: 10792060

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Abstract

Phosphorylation of the regulatory (R) domain initiates cystic fibrosis transmembrane conductance regulator (CFTR) Cl − channel activity. To discover how the function of this domain is determined by its structure, we produced an R domain protein (R8) that spanned residues 708–831 of CFTR. Phosphorylated, but not unphosphorylated, R8 stimulated activity of CFTR channels lacking this domain, indicating that R8 is functional. Unexpectedly, this functional R8 was predominantly random coil, as revealed by CD and limited proteolysis. The CD spectra of both phosphorylated and nonphosphorylated R8 were similar in aqueous buffer. The folding agent trimethylamine N -oxide induced only a small increase in the helical content of nonphosphorylated R8 and even less change in the helical content of phosphorylated R8. These data, indicating that the R domain is predominantly random coil, may explain the seemingly complex way in which phosphorylation regulates CFTR channel activity.

Biological Sciences

Details

Title: Subtitle: A functional R domain from cystic fibrosis transmembrane conductance regulator is predominantly unstructured in solution
Creators: Lynda S Ostedgaard - Howard Hughes Medical Institute
Olafur Baldursson - Howard Hughes Medical Institute
Daniel W Vermeer - Howard Hughes Medical Institute
Michael J Welsh - Howard Hughes Medical Institute
Andrew D Robertson - Howard Hughes Medical Institute
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.97(10), pp.5657-5662
DOI: 10.1073/pnas.100588797
PMID: 10792060
PMCID: PMC25884
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 05/09/2000
Academic Unit: Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Neurosurgery; Internal Medicine
Record Identifier: 9984017166502771

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