pH Dependence of structural stability of interleukin-2 and granulocyte colony-stimulating factor

摘要: After a cytokine binds to its receptor on the cell surface (pH ~7), complex is internalized into acidic endosomal compartments ~5–6), where partially unfolded intermediates can form. The nature of these structural transitions was studied for wild-type interleukin-2 (IL-2) and granulocyte colony-stimulating factor (G-CSF). A noncoincidence denaturation in secondary tertiary structure IL-2 perturbations G-CSF suggest presence an intermediate state each, common feature this family four-helical bundle proteins. Unexpectedly, both display monotonic increases stability as pH decreased from 7 4. We hypothesize that such cytokines with cell-based clearance mechanisms vivo may have evolved help stabilize complexes sorting lysosomal degradation. show mutants differential stabilities their counterparts function pH, differences explain ligand trafficking depletion. Further understanding changes accompanying unfolding guide design respect binding, endocytic trafficking, and, consequently, therapeutic efficacy.