Selenoprotein K binds multiprotein complexes and is involved in the regulation of endoplasmic reticulum homeostasis.
Selenoprotein K (SelK) is an 11-kDa endoplasmic reticulum (ER) protein of unknown function. Herein, we defined a new eukaryotic protein family that includes SelK, selenoprotein S (SelS), and distantly related proteins. Comparative genomics analyses indicate that this family is the most widespread eukaryotic selenoprotein family. A biochemical search for proteins that interact with SelK revealed ER-associated degradation (ERAD) components (p97 ATPase, Derlins, and SelS). In this complex, SelK showed higher affinity for Derlin-1, whereas SelS had higher affinity for Derlin-2, suggesting that these selenoproteins could determine the nature of the substrate translocated through the Derlin channel. SelK co-precipitated with soluble glycosylated ERAD substrates and was involved in their degradation. Its gene contained a functional ER stress response element, and its expression was up-regulated by conditions that induce the accumulation of misfolded proteins in the ER. Components of the oligosaccharyltransferase complex (ribophorins, OST48, and STT3A) and an ER chaperone, calnexin, were found to bind SelK. A glycosylated form of SelK was also detected, reflecting its association with the oligosaccharyltransferase complex. These data suggest that SelK is involved in the Derlin-dependent ERAD of glycosylated misfolded proteins and that the function defined by the prototypic SelK is the widespread function of selenium in eukaryotes.
Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Valentina A
VA
Shchedrina
Robert A
RA
Everley
Yan
Y
Zhang
Steven P
SP
Gygi
Dolph L
DL
Hatfield
Vadim N
VN
Gladyshev
D015153:Blotting, Western; D002460:Cell Line; D002853:Chromatography, Liquid; D019295:Computational Biology; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017510:Protein Folding; D051140:Selenoproteins / Q000235:genetics / Q000378:metabolism*; D013880:Thioredoxin-Disulfide Reductase / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
C487709:DERL1 protein, human; C513305:DERL2 protein, human; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D051140:Selenoproteins; D014415:Tunicamycin; D013880:Thioredoxin-Disulfide Reductase