Interleukin-11 binds specific EF-hand proteins via their conserved structural motifs
Interleukin-11 binds specific EF-hand proteins via their conserved structural motifs
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DOI：
10.1080/07391102.2015.1132392
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发表时间：
2017-01-01
影响因子：
4.4
通讯作者：
Permyakov, Sergei E.
中科院分区：
文献类型：
--
作者：
Kazakov, Alexei S.;Sokolov, Andrei S.;Permyakov, Sergei E.
白细胞介素-11（IL-11）是参与许多生物过程的造血细胞因子，并且被验证为用于治疗各种癌症的靶标。IL-11含有可能识别多个靶标的内在无序区域。最近我们发现IL-11除了与gp 130和RA受体相互作用外，还与钙敏感蛋白S100 P相互作用。这种相互作用的严格钙依赖性表明IL-11与其他钙传感器蛋白相互作用的可能性。在这里，我们探测了IL-11对各种类型的钙结合蛋白的特异性：EF-手家族的钙传感器（钙调蛋白，S100 B和神经元钙传感器：恢复蛋白，NCS-1，GCAP-1，GCAP-2），EF-手家族的钙缓冲液（S100 G，oncomodulin），和非EF-手钙缓冲液（-乳白蛋白）。钙传感器蛋白质的特定子集（钙调蛋白、S100 B、NCS-1、GCAP-1/2）表现出IL-11的金属依赖性结合，解离常数为1- 19 M。这些蛋白质共享属于EF-手蛋白的保守结构基序的几个氨基酸残基，黑色和灰色簇。用丙氨酸替换相应的S100 P残基显著降低了其对IL-11的亲和力，表明它们参与了缔合过程。研究的EF-手蛋白的铰链区的二级结构和可及性被预测控制其与IL-11结合的特异性和选择性。预期IL-11与EF-手蛋白的相互作用在许多病理条件下发生，伴随着质膜的崩解和细胞组分流出到细胞外环境中。
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 (-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 1-19M. 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.