title: A conserved sugar bridge connected to the WSXWS motif has an important role for transport of IL-21R to the plasma membrane.
abstract: Interleukin-21 (IL-21) is a class I cytokine that belongs to the γc-subfamily of cytokines and regulates immune responses. It signals through a heterodimeric receptor complex composed of the IL-21R1 and γc-receptor chains. A characteristic feature of class I cytokine receptors is the presence of a consensus motif WSXWS (WS motif) in the membrane proximal fibronectin type III domain (FNIII) of these receptors. We recently described the structure of the IL-21R:IL-21 complex and showed that the first tryptophan of the WS motif of IL-21R is mannosylated and involved in formation of a sugar bridge that connects the two FNIII domains of the receptor. Furthermore, a mutation within the WS motif of IL-21R was recently shown to cause a novel kind of primary immunodeficiency syndrome (PID). Here, we report the structure of IL-21R alone, which shows that the sugar bridge forms independently of whether IL-21R binds IL-21 or not, and we furthermore investigate the role of this bridge in the export of IL-21R and γC to the plasma membrane. Thus, we provide a molecular explanation for how mutations in the WS motif may cause PIDs.
authors.affiliation: Department of Molecular Biology and Genetics, University of Aarhus, Aarhus, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Siupka
authors.affiliation: Department of Molecular Biology and Genetics, University of Aarhus, Aarhus, Denmark.
authors.forename: O T
authors.initials: OT
authors.lastname: Hamming
authors.affiliation: Novo Nordisk R&D Center China, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Kang
authors.affiliation: Department of Molecular Biology and Genetics, University of Aarhus, Aarhus, Denmark.
authors.forename: H H
authors.initials: HH
authors.lastname: Gad
authors.affiliation: Department of Molecular Biology and Genetics, University of Aarhus, Aarhus, Denmark.
authors.forename: R
authors.identifier: http://orcid.org/0000-0003-1159-066X
authors.initials: R
authors.lastname: Hartmann
mesh_terms: D020816:Amino Acid Motifs; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007378:Interleukins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D053655:Receptors, Interleukin-21 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000378:metabolism; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D005353:Fibronectins; D007378:Interleukins; D053655:Receptors, Interleukin-21; C501364:fibronectin type III like peptide, human; D014364:Tryptophan; D000098546:Interleukin-21