| Popis: |
Publisher Summary 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-6Rα, and a common chain, gp130, which is shared by other cytokine receptor complexes. The IL-6 receptor complex differs distinctly from the heterodimeric γC cytokine complexes in the sense that the gp130 chain by itself constitutes the signaling receptor subunit, while IL-6Rα 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. |
