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J Biomol Struct Dyn. 2017 Jan;35(1):78-91. doi: 10.1080/07391102.2015.1132392. Epub 2016 Mar 8.

Interleukin-11 binds specific EF-hand proteins via their conserved structural motifs.

Author information

1
a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.
2
b Faculty of Science and Engineering , Åbo Akademi University , Biskopsgatan 8, Åbo 20500 , Finland.
3
c Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University , Leninskye Gory, House 1, Building 40, Moscow 119992 , Russia.
4
d Branch of Shemyakin and Ovchinnikov , Institute of Bioorganic Chemistry of the Russian Academy of Sciences , Institutskaya str. 6, Pushchino, Moscow Region 142290 , Russia.
5
e CJSC R-Pharm , Berzarina str., 19/1, Moscow 123154 , Russia.
6
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.
7
g Antherix , Institutskaya str. 7, Pushchino, Moscow Region 142290 , Russia.
8
h Biomirex Inc. , 304 Pleasant Street, Watertown , MA 02472 , USA.

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.

KEYWORDS:

EF-hand; S100 protein; cancer; interleukin; intrinsic disorder; neuronal calcium sensor; protein–protein interaction

PMID:
26726132
DOI:
10.1080/07391102.2015.1132392
[Indexed for MEDLINE]

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