The novel CXCL12gamma isoform encodes an unstructured cationic domain which regulates bioactivity and interaction with both glycosaminoglycans and CXCR4.
The novel CXCL12gamma isoform encodes an unstructured cationic domain which regulates bioactivity and interaction with both glycosaminoglycans and CXCR4.
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新型的CXCL12GAMMA同工型编码一个非结构化的阳离子结构域，该结构域调节了与糖胺聚糖和CXCR4的生物活性和相互作用。
DOI：
10.1371/journal.pone.0001110
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发表时间：
2007-10-31
期刊：
影响因子：
3.7
通讯作者：
Lortat-Jacob, Hugues
中科院分区：
文献类型：
--
作者：
Laguri, Cedric;Sadir, Rabia;Rueda, Patricia;Baleux, Francoise;Gans, Pierre;Arenzana-Seisdedos, Fernando;Lortat-Jacob, Hugues
CXCL12α是一种趋化因子，可促进多种细胞的定向迁移和组织归巢，通过与其同源受体(CXCR4)和硫酸乙酰肝素(HS)的相互作用调节关键的体内平衡功能和病理过程。CXCL12基因的选择性剪接产生了最近发现的CXCL12γ异构体，其结构/功能关系尚不清楚。然而，这种异构体的高碱性残基的出现表明，它可能具有HS的特异性调节。利用表面等离子体共振和核磁共振光谱，以及化学和重组产生的趋化因子，我们在这里证明了CXCL12γ前68个氨基酸采用了与所描述的α异构体密切相关的结构，随后是30个氨基酸的未折叠C末端延伸。值得注意的是，这些残基中60%是赖氨酸或精氨酸，其中大多数聚集在典型的HS结合部位。这提供了迄今观察到的对HP具有最高亲和力的趋化因子(Kd = 0.9nM)，并确保趋化因子在细胞表面的强烈保留。这是由于两个合作结合位点的独特结合，一个是严格要求的，在蛋白质的结构域中找到，另一个是C-末端，主要通过延长复合体的半衰期发挥作用。重要的是，这个特殊的C末端还调节HS和CXCR4结合之间的平衡，从而调节趋化因子的生物活性。总而言之，这些数据描述了一种不寻常的结合过程，它导致趋化因子和HS之间前所未有的高亲和力。这表明CXCL12的γ异构体具有独特的结构和功能特性，经过优化以确保其在细胞表面的强大保持。因此，根据其结合的趋化因子亚型，HS可以不同地协调CXCL12介导的定向细胞运动。
CXCL12α, a chemokine that importantly promotes the oriented cell migration and tissue homing of many cell types, regulates key homeostatic functions and pathological processes through interactions with its cognate receptor (CXCR4) and heparan sulfate (HS). The alternative splicing of the cxcl12 gene generates a recently identified isoform, CXCL12γ, which structure/function relationships remain unexplored. The high occurrence of basic residues that characterize this isoform suggests however that it could feature specific regulation by HS. Using surface plasmon resonance and NMR spectroscopy, as well as chemically and recombinantly produced chemokines, we show here that CXCL12γ first 68 amino acids adopt a structure closely related to the well described α isoform, followed by an unfolded C-terminal extension of 30 amino acids. Remarkably, 60 % of these residues are either lysine or arginine, and most of them are clustered in typical HS binding sites. This provides the chemokine with the highest affinity for HP ever observed (Kd = 0.9 nM), and ensures a strong retention of the chemokine at the cell surface. This was due to the unique combination of two cooperative binding sites, one strictly required, found in the structured domain of the protein, the other one being the C-terminus which essentially functions by enhancing the half life of the complexes. Importantly, this peculiar C-terminus also regulates the balance between HS and CXCR4 binding, and consequently the biological activity of the chemokine. Together these data describe an unusual binding process that gives rise to an unprecedented high affinity between a chemokine and HS. This shows that the γ isoform of CXCL12, which features unique structural and functional properties, is optimized to ensure its strong retention at the cell surface. Thus, depending on the chemokine isoform to which it binds, HS could differentially orchestrate the CXCL12 mediated directional cell kinesis.
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影响因子：
5.4
作者：
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通讯作者：
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