title: Role for phospholipid interactions in the trafficking defect of Delta F508-CFTR.
abstract: Cystic fibrosis commonly occurs as a consequence of the DeltaF508 mutation in the first nucleotide binding fold domain (NBF-1) of CFTR. The mutation causes retention of the mutant CFTR molecule in the endoplasmic reticulum, and this aberrant trafficking event is believed to be due to defective interactions between the mutant NBF-1 domain and other cellular factors in the endoplasmic reticulum. Since the NBF-1 domain has been shown to interact with membranes, we wanted to investigate whether NBF-1 and CFTR interactions with specific phospholipid chaperones might play a role in trafficking. We have found that the recombinant wild-type NBF-1 interacts selectively with phosphatidylserine (PS) rather than phosphatidylcholine (PC). By contrast, NBF-1 carrying the DeltaF508 mutation loses the ability to discriminate between these two phospholipids. In cells expressing DeltaF508-CFTR, replacement of PC by noncharged analogues results in an absolute increase in CFTR expression. In addition, we detected progressive expression of higher molecular weight CFTR forms. Thus, phospholipid chaperones may be important for CFTR trafficking, and contribute to the pathology of cystic fibrosis.
authors.affiliation: Department of Anatomy, Physiology, and Genetics, and Institute for Molecular Medicine, USUHS, Bethesda, Maryland 20814, USA.
authors.forename: Ofer
authors.initials: O
authors.lastname: Eidelman
authors.forename: Shoshana
authors.initials: S
authors.lastname: BarNoy
authors.forename: Michal
authors.initials: M
authors.lastname: Razin
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhang
authors.forename: Peter
authors.initials: P
authors.lastname: McPhie
authors.forename: George
authors.initials: G
authors.lastname: Lee
authors.forename: Zhen
authors.initials: Z
authors.lastname: Huang
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorscher
authors.forename: Harvey B
authors.initials: HB
authors.lastname: Pollard
mesh_terms: D000605:Amino Alcohols / Q000737:chemistry; D000818:Animals; D002942:Circular Dichroism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D004983:Ethanolamines / Q000737:chemistry; D006801:Humans; D007739:L Cells; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D009154:Mutation; D009711:Nucleotides / Q000737:chemistry; D010539:Permeability; D010649:Phenylalanine / Q000235:genetics; D010713:Phosphatidylcholines / Q000737:chemistry / Q000502:physiology; D010718:Phosphatidylserines / Q000737:chemistry / Q000502:physiology; D010743:Phospholipids / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D011412:Propanolamines / Q000737:chemistry; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D013050:Spectrometry, Fluorescence
chemical_list: D000605:Amino Alcohols; C505032:CFTR protein, human; D004983:Ethanolamines; D008081:Liposomes; D009711:Nucleotides; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D010743:Phospholipids; D011412:Propanolamines; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C109550:3-amino-1-propanol; D010649:Phenylalanine; C006506:2-amino-1-butanol; C017500:N-methylaminoethanol