title: Interleukin-11 binds specific EF-hand proteins via their conserved structural motifs.
abstract: Interleukin-11 (IL-11) is a hematopoietic cytokine engaged in numerous biological processes and validated as a target for treatment of various cancers. IL-11 contains intrinsically disordered regions that might recognize multiple targets. Recently we found that aside from IL-11RA and gp130 receptors, IL-11 interacts with calcium sensor protein S100P. Strict calcium dependence of this interaction suggests a possibility of IL-11 interaction with other calcium sensor proteins. Here we probed specificity of IL-11 to calcium-binding proteins of various types: calcium sensors of the EF-hand family (calmodulin, S100B and neuronal calcium sensors: recoverin, NCS-1, GCAP-1, GCAP-2), calcium buffers of the EF-hand family (S100G, oncomodulin), and a non-EF-hand calcium buffer (α-lactalbumin). A specific subset of the calcium sensor proteins (calmodulin, S100B, NCS-1, GCAP-1/2) exhibits metal-dependent binding of IL-11 with dissociation constants of 1-19 μM. These proteins share several amino acid residues belonging to conservative structural motifs of the EF-hand proteins, 'black' and 'gray' clusters. Replacements of the respective S100P residues by alanine drastically decrease its affinity to IL-11, suggesting their involvement into the association process. Secondary structure and accessibility of the hinge region of the EF-hand proteins studied are predicted to control specificity and selectivity of their binding to IL-11. The IL-11 interaction with the EF-hand proteins is expected to occur under numerous pathological conditions, accompanied by disintegration of plasma membrane and efflux of cellular components into the extracellular milieu.
authors.affiliation: a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.
authors.forename: Alexei S
authors.initials: AS
authors.lastname: Kazakov
authors.affiliation: a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.
authors.forename: Andrei S
authors.initials: AS
authors.lastname: Sokolov
authors.affiliation: a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.
authors.forename: Alisa A
authors.initials: AA
authors.lastname: Vologzhannikova
authors.affiliation: a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Permyakova
authors.affiliation: a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.
authors.forename: Polina A
authors.initials: PA
authors.lastname: Khorn
authors.affiliation: a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.
authors.forename: Ramis G
authors.initials: RG
authors.lastname: Ismailov
authors.affiliation: b Faculty of Science and Engineering , Åbo Akademi University , Biskopsgatan 8, Åbo 20500 , Finland.
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Denessiouk
authors.affiliation: a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.|b Faculty of Science and Engineering , Åbo Akademi University , Biskopsgatan 8, Åbo 20500 , Finland.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Denesyuk
authors.affiliation: a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Rastrygina
authors.affiliation: c Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University , Leninskye Gory, House 1, Building 40, Moscow 119992 , Russia.
authors.forename: Viktoriia E
authors.initials: VE
authors.lastname: Baksheeva
authors.affiliation: c Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University , Leninskye Gory, House 1, Building 40, Moscow 119992 , Russia.
authors.forename: Evgeni Yu
authors.initials: EY
authors.lastname: Zernii
authors.affiliation: d Branch of Shemyakin and Ovchinnikov , Institute of Bioorganic Chemistry of the Russian Academy of Sciences , Institutskaya str. 6, Pushchino, Moscow Region 142290 , Russia.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Zinchenko
authors.affiliation: e CJSC R-Pharm , Berzarina str., 19/1, Moscow 123154 , Russia.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Glazatov
authors.affiliation: a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.|f Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine , University of South Florida , Tampa , FL 33612 , USA.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
authors.affiliation: g Antherix , Institutskaya str. 7, Pushchino, Moscow Region 142290 , Russia.|h Biomirex Inc. , 304 Pleasant Street, Watertown , MA 02472 , USA.
authors.forename: Tajib A
authors.initials: TA
authors.lastname: Mirzabekov
authors.affiliation: a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Permyakov
authors.affiliation: a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.
authors.forename: Sergei E
authors.initials: SE
authors.lastname: Permyakov
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry*; D017124:Conserved Sequence; D020832:EF Hand Motifs; D006801:Humans; D017370:Interleukin-11 / Q000737:chemistry* / Q000378:metabolism; D008670:Metals / Q000737:chemistry; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D054730:Protein Interaction Domains and Motifs
chemical_list: D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D017370:Interleukin-11; D008670:Metals; D009363:Neoplasm Proteins; C103003:S100P protein, human
keywords: EF-hand; S100 protein; cancer; interleukin; intrinsic disorder; neuronal calcium sensor; protein–protein interaction