title: Structural and functional changes in a synthetic S5 segment of KvLQT1 channel as a result of a conserved amino acid substitution that occurs in LQT1 syndrome of human.
abstract: Mutations in various voltage gated cardiac ion channels are the cause of different forms of long QT syndrome (LQTS), which is an inherited arrhythmic disorder marked as a prolonged QT interval on electrocardiogram. Of these LQTS1 is associated with mutations in the gene encoding KCNQ1 (KvLQT1) channel. One responsible mutation, G269S, in the S5 segment of KvLQT1, that affects the proper expression and function of channel protein leads to LQTS1. Our objective was to study how G269S mutation interferes with the structure and function of a synthetic S5 segment of KvLQT1 channel. One wild type 22-residue peptide and another mutant peptide of the same length with G269S mutation, derived from the S5 segment were synthesized and labeled with fluorescent probes. The mutant peptide exhibited lower affinity towards phospholipid vesicles as compared to the wild type peptide and showed impaired assembly and localization onto the lipid vesicles as evidenced by membrane-binding, energy transfer and proteolytic cleavage experiments. Loss in the helical content of S5 mutant peptide in membrane-mimetic environments was observed. Furthermore, it was observed that G269S mutation significantly inhibited the ability of S5 peptide to permeabilize the lipid vesicles. The present studies show the basis of change in function of the selected S5 segment as a result of G269S mutation which is associated with LQT1 syndrome. We speculate that the structural and functional changes related to the glycine to serine amino acid substitution in the S5 segment may also influence the activity of the whole KvLQT1 channel.
authors.affiliation: Molecular and Structural Biology Division, Central Drug Research Institute, CSIR, Lucknow-226001, India.
authors.forename: Richa
authors.initials: R
authors.lastname: Verma
authors.forename: Jimut Kanti
authors.initials: JK
authors.lastname: Ghosh
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D017124:Conserved Sequence; D019286:Endopeptidase K / Q000378:metabolism; D005453:Fluorescence; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008081:Liposomes / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010069:Oxadiazoles / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D010539:Permeability; D010713:Phosphatidylcholines / Q000378:metabolism; D010715:Phosphatidylglycerols / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: C526864:7-nitrobenz-2-oxa-1,3-diazole; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D008081:Liposomes; D050505:Mutant Proteins; D010069:Oxadiazoles; D010455:Peptides; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D019286:Endopeptidase K