title: Voltage sensor mutations differentially target misfolded K+ channel subunits to proteasomal and non-proteasomal disposal pathways.
abstract: In Shaker K(+) channels, formation of an electrostatic interaction between two charged residues, D316 and K374 in transmembrane segments S3 and S4, respectively, is a key step in voltage sensor biogenesis. Mutations D316K and K374E disrupt formation of the voltage sensor and lead to endoplasmic reticulum retention. We have now investigated the fates of these misfolded proteins. Both are significantly less stable than the wild-type protein. D316K is degraded by cytoplasmic proteasomes, whereas K374E is degraded by a lactacystin-insensitive, non-proteasomal pathway. Our results suggest that the D316K and K374E proteins are misfolded in recognizably different ways, an observation with implications for voltage sensor biogenesis.
authors.affiliation: Department of Physiology and Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Box 951751, Los Angeles, CA 90095-1751, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Myers
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
authors.forename: Eun Jeon
authors.initials: EJ
authors.lastname: Lee
authors.forename: Diane M
authors.initials: DM
authors.lastname: Papazian
mesh_terms: D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D017510:Protein Folding
chemical_list: D009097:Multienzyme Complexes; D015221:Potassium Channels; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex