NDLI: Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis.

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Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Skalak, Timothy Wang, Chi Hunt, John F. Spencer Emtage, J. Seehausen, Derek Atwell, Shane Yang, Zhengrong Wetmore, Diana R. Zhao, Xun Brouillette, Christie G. Protasevich, Irina
Description	Country affiliation: United States Author Affiliation: Wang C ( Department of Biological Sciences, 702A Fairchild Center, Columbia University, New York, New York 10027, USA.)
Abstract	The lethal genetic disease cystic fibrosis is caused predominantly by in-frame deletion of phenylalanine 508 in the cystic fibrosis transmembrane conductance regulator (CFTR). F508 is located in the first nucleotide-binding domain (NBD1) of CFTR, which functions as an ATP-gated chloride channel on the cell surface. The F508del mutation blocks CFTR export to the surface due to aberrant retention in the endoplasmic reticulum. While it was assumed that F508del interferes with NBD1 folding, biophysical studies of purified NBD1 have given conflicting results concerning the mutation's influence on domain folding and stability. We have conducted isothermal (this paper) and thermal (accompanying paper) denaturation studies of human NBD1 using a variety of biophysical techniques, including simultaneous circular dichroism, intrinsic fluorescence, and static light-scattering measurements. These studies show that, in the absence of ATP, NBD1 unfolds via two sequential conformational transitions. The first, which is strongly influenced by F508del, involves partial unfolding and leads to aggregation accompanied by an increase in tryptophan fluorescence. The second, which is not significantly influenced by F508del, involves full unfolding of NBD1. Mg-ATP binding delays the first transition, thereby offsetting the effect of F508del on domain stability. Evidence suggests that the initial partial unfolding transition is partially responsible for the poor in vitro solubility of human NBD1. Second-site mutations that increase the solubility of isolated F508del-NBD1 in vitro and suppress the trafficking defect of intact F508del-CFTR in vivo also stabilize the protein against this transition, supporting the hypothesize that it is responsible for the pathological trafficking of F508del-CFTR.
ISSN	09618368
e-ISSN	1469896X
DOI	10.1002/pro.480
Journal	Protein Science
Issue Number	10
Volume Number	19
Language	English
Publisher	Wiley-Blackwell (on behalf of The Protein Society)
Publisher Date	2010-10-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Cystic Fibrosis Transmembrane Conductance Regulator Chemistry Cystic Fibrosis Genetics Mutation Protein Folding Adenosine Triphosphate Pharmacology Biophysical Phenomena Circular Dichroism Models, Molecular Phenylalanine Protein Conformation Drug Effects Protein Denaturation Protein Structure, Tertiary Sequence Deletion Solubility Spectrometry, Fluorescence Temperature Research Support, Non-u.s. Gov't Discipline Biochemistry
Content Type	Text
Resource Type	Article
Subject	Medicine Molecular Biology Biochemistry

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Thermal unfolding simulations of NBD1 domain variants reveal structural motifs associated with the impaired folding of F508del-CFTR

Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1.

Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis

Folding and Rescue of a Cystic Fibrosis Transmembrane Conductance Regulator Trafficking Mutant Identified Using Human-Murine Chimeric Proteins

Deletion of Phenylalanine 508 in the First Nucleotide-binding Domain of the Cystic Fibrosis Transmembrane Conductance Regulator Increases Conformational Exchange and Inhibits Dimerization

Conformational Changes Relevant to Channel Activity and Folding within the first Nucleotide Binding Domain of the Cystic Fibrosis Transmembrane Conductance Regulator

Non-native Conformers of Cystic Fibrosis Transmembrane Conductance Regulator NBD1 Are Recognized by Hsp27 and Conjugated to SUMO-2 for Degradation

C Terminus of Nucleotide Binding Domain 1 Contains Critical Features for Cystic Fibrosis Transmembrane Conductance Regulator Trafficking and Activation

A recombinant peptide model of the first nucleotide-binding fold of the cystic fibrosis transmembrane conductance regulator: comparison of wild-type and delta F508 mutant forms.

Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis.

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