Interaction of S100A6 Protein with the Four-Helical Cytokines
Alexey S. Kazakov,
Evgenia I. Deryusheva,
Victoria A. Rastrygina,
Andrey S. Sokolov,
Maria E. Permyakova,
Ekaterina A. Litus,
Vladimir N. Uversky,
Eugene A. Permyakov,
Sergei E. Permyakov
Affiliations
Alexey S. Kazakov
Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia
Evgenia I. Deryusheva
Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia
Victoria A. Rastrygina
Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia
Andrey S. Sokolov
Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia
Maria E. Permyakova
Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia
Ekaterina A. Litus
Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia
Vladimir N. Uversky
Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia
Eugene A. Permyakov
Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia
Sergei E. Permyakov
Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia
S100 is a family of over 20 structurally homologous, but functionally diverse regulatory (calcium/zinc)-binding proteins of vertebrates. The involvement of S100 proteins in numerous vital (patho)physiological processes is mediated by their interaction with various (intra/extra)cellular protein partners, including cell surface receptors. Furthermore, recent studies have revealed the ability of specific S100 proteins to modulate cell signaling via direct interaction with cytokines. Previously, we revealed the binding of ca. 71% of the four-helical cytokines via the S100P protein, due to the presence in its molecule of a cytokine-binding site overlapping with the binding site for the S100P receptor. Here, we show that another S100 protein, S100A6 (that has a pairwise sequence identity with S100P of 35%), specifically binds numerous four-helical cytokines. We have studied the affinity of the recombinant forms of 35 human four-helical cytokines from all structural families of this fold to Ca2+-loaded recombinant human S100A6, using surface plasmon resonance spectroscopy. S100A6 recognizes 26 of the cytokines from all families of this fold, with equilibrium dissociation constants from 0.3 nM to 12 µM. Overall, S100A6 interacts with ca. 73% of the four-helical cytokines studied to date, with a selectivity equivalent to that for the S100P protein, with the differences limited to the binding of interleukin-2 and oncostatin M. The molecular docking study evidences the presence in the S100A6 molecule of a cytokine-binding site, analogous to that found in S100P. The findings argue the presence in some of the promiscuous members of the S100 family of a site specific to a wide range of four-helical cytokines. This unique feature of the S100 proteins potentially allows them to modulate the activity of the numerous four-helical cytokines in the disorders accompanied by an excessive release of the cytokines.
