Structural basis of a chemokine heterodimer binding to glycosaminoglycans.
Structural basis of a chemokine heterodimer binding to glycosaminoglycans.
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趋化因子异二聚体与糖胺聚糖结合的结构基础。
DOI：
10.1042/bcj20200927
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Rajarathnam,Krishna
中科院分区：
文献类型：
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作者：
Sepuru,KrishnaMohan;Rajarathnam,Krishna
趋化因子Cxcl1/KC和Cxcl2/MIP2在协调中性粒细胞向损伤部位的迁移中起着至关重要的作用。趋化因子的募集活性受单体-二聚体平衡和与糖胺聚糖（GAGs）结合的调节。GAG链与蛋白多糖（pg）的核心蛋白共价连接，在炎症反应中也作为肝素酶切割的自由链存在。与游离GAGs相比，PG中与GAGs的结合受到其共价键和受限迁移性的固定方向性的影响。GAG相互作用影响趋化因子单体/二聚体水平、趋化和趋化梯度、寿命和受体结合的呈现。在这里，我们发现Cxcl1和Cxcl2也形成异源二聚体。利用二硫化物捕获的Cxcl1-Cxcl2异质二聚体，利用核磁共振和等温滴定量热法表征了其与游离肝素的结合，并利用表面等离子体共振表征了其与固定化肝素和硫酸肝素的结合。这些数据，结合分子对接，表明异源二聚体的结合特征，如几何和化学计量，在自由和固定的gag之间是不同的，也明显不同于同型二聚体。我们认为，异二聚体结构的内在不对称性，以及其与PG GAGs和游离GAGs结合的差异，调节了趋化因子的功能。
Chemokines Cxcl1/KC and Cxcl2/MIP2 play a crucial role in coordinating neutrophil migration to the insult site. Chemokines’ recruitment activity is regulated by monomer–dimer equilibrium and binding to glycosaminoglycans (GAGs). GAG chains exist as covalently linked to core proteins of proteoglycans (PGs) and also as free chains due to cleavage by heparanases during the inflammatory response. Compared with free GAGs, binding to GAGs in a PG is influenced by their fixed directionality due to covalent linkage and restricted mobility. GAG interactions impact chemokine monomer/dimer levels, chemotactic and haptotactic gradients, life time, and presentation for receptor binding. Here, we show that Cxcl1 and Cxcl2 also form heterodimers. Using a disulfide-trapped Cxcl1–Cxcl2 heterodimer, we characterized its binding to free heparin using nuclear magnetic resonance and isothermal titration calorimetry, and to immobilized heparin and heparan sulfate using surface plasmon resonance. These data, in conjunction with molecular docking, indicate that the binding characteristics such as geometry and stoichiometry of the heterodimer are different between free and immobilized GAGs and are also distinctly different from those of the homodimers. We propose that the intrinsic asymmetry of the heterodimer structure, along with differences in its binding to PG GAGs and free GAGs, regulate chemokine function.