Lishan Kang

Amedeo Avogadro University of Eastern Piedmont, Novara, Piedmont, Italy

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Publications (6)19.3 Total impact

  • P Siupka · O T Hamming · L Kang · H H Gad · R Hartmann
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    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.Genes and Immunity advance online publication, 4 June 2015; doi:10.1038/gene.2015.22.
    No preview · Article · Jun 2015 · Genes and immunity
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    ABSTRACT: IL-21 is a class I cytokine that exerts pleiotropic effects on both innate and adaptive immune responses. It signals through a heterodimeric receptor complex consisting of the IL-21 receptor (IL-21R) and the common γ-chain. A hallmark of the class I cytokine receptors is the class I cytokine receptor signature motif (WSXWS). The exact role of this motif has not been determined yet; however, it has been implicated in diverse functions, including ligand binding, receptor internalization, proper folding, and export, as well as signal transduction. Furthermore, the WXXW motif is known to be a consensus sequence for C-mannosylation. Here, we present the crystal structure of IL-21 bound to IL-21R and reveal that the WSXWS motif of IL-21R is C-mannosylated at the first tryptophan. We furthermore demonstrate that a sugar chain bridges the two fibronectin domains that constitute the extracellular domain of IL-21R and anchors at the WSXWS motif through an extensive hydrogen bonding network, including mannosylation. The glycan thus transforms the V-shaped receptor into an A-frame. This finding offers a novel structural explanation of the role of the class I cytokine signature motif.
    Full-text · Article · Jan 2012 · Journal of Biological Chemistry

  • No preview · Article · Oct 2011 · Cytokine
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    ABSTRACT: The cytokine interleukin (IL)-21 exerts pleiotropic effects acting through innate as well as adaptive immune responses. The activities of IL-21 are mediated through binding to its cognate receptor complex composed of the IL-21 receptor private chain (IL-21Rα) and the common γ-chain (γC), the latter being shared by IL-2, IL-4, IL-7, IL-9, and IL-15. The binding energy of the IL-21 ternary complex is predominantly provided by the high affinity interaction between IL-21 and IL-21Rα, whereas the interaction between IL-21 and γC, albeit essential for signaling, is rather weak. The design of IL-21 analogues, which have lost most or all affinity toward the signaling γC chain, while simultaneously maintaining a tight interaction with the private chain, would in theory represent candidates for IL-21 antagonists. We predicted the IL-21 residues, which compose the γC binding epitope using homology modeling and alignment with the related cytokines, IL-2 and IL-4. Next we systematically analyzed the predicted binding epitope by a mutagenesis study. Indeed two mutants, which have significantly impaired γC affinity with undiminished IL-21Rα affinity, were successfully identified. Functional studies confirmed that these two novel hIL-21 double mutants do act as hIL-21 antagonists.
    Full-text · Article · Feb 2010 · Journal of Biological Chemistry
  • Kent Bondensgaard · Lishan Kang · Siv A. Hjorth
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    ABSTRACT: This chapter focuses on cytokine variants which have distinguished themselves by exhibiting altered biological activity compared to the naturally occurring (wt) cytokine in terms of enhanced potency in biological assays. It also emphasizes the identification of super-agonists, which arise from the exchange of amino acid residues within the cytokine protein per se. The growth hormone (hGH) is a monomeric protein, and binds the hGH receptor in a 1:2 ratio via two non-identical sites, called sites 1 and 2. Variants of hGH exhibiting improved binding affinity to the hGH receptor have been identified through an extensive affinity maturation approach, and one such "super-binding" variant, hGH, encompassing a total of 15 single-substitutions, has been demonstrated to bind with a 400-fold enhanced affinity to the hGH receptor. A saturation mutagenesis employing a minimized yet fully active form of IL-3 has revealed that 1-2 percent out of a total of more than 700 individual single-site mutants exhibited enhanced activity, emphasizing that the naturally occurring cytokine represents but one active form of the protein molecule, albeit not the most active form. The cytokine IL-6 signals through a receptor complex composed of a selective chain, IL-6R?, and a common chain, gp130, which is shared by other cytokine receptor complexes. The IL-6 receptor complex differs distinctly from the heterodimeric αC cytokine complexes in the sense that the gp130 chain by itself constitutes the signaling receptor subunit, while IL-6R? solely provides affinity and even does so either in cis, when membrane-embedded along with gp130, or in trans, when present in solution or on another cell.
    No preview · Article · Jan 2010
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    ABSTRACT: The high resolution three-dimensional structure of human interleukin (hIL)-21 has been resolved by heteronuclear NMR spectroscopy. Overall, the hIL-21 structure is dominated by a well defined central four-helical bundle, arranged in an up-up-down-down topology, as observed for other cytokines. A segment of the hIL-21 molecule that includes the third helical segment, helix C, is observed to exist in two distinct and interchangeable states. In one conformer, the helix C segment is presented in a regular, α-helical conformation, whereas in the other conformer, this segment is largely disordered. A structure-based sequence alignment of hIL-21 with receptor complexes of the related cytokines, interleukin-2 and -4, implied that this particular segment is involved in receptor binding. An hIL-21 analog was designed to stabilize the region around helix C through the introduction of a segment grafted from hIL-4. This novel hIL-21 analog was demonstrated to exhibit a 10-fold increase in potency in a cellular assay.
    Preview · Article · Sep 2007 · Journal of Biological Chemistry