Panels of chemically-modified heparin polysaccharides and natural heparan sulfate saccharides both exhibit differences in binding to Slit and Robo, as well as variation between protein binding and cellular activity.
Panels of chemically-modified heparin polysaccharides and natural heparan sulfate saccharides both exhibit differences in binding to Slit and Robo, as well as variation between protein binding and cellular activity.
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DOI：
10.1039/c6mb00432f
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发表时间：
2016-10-20
影响因子：
--
通讯作者：
Powell AK
中科院分区：
文献类型：
--
作者：
Ahmed YA;Yates EA;Moss DJ;Loeven MA;Hussain SA;Hohenester E;Turnbull JE;Powell AK
肝素/硫酸乙酰肝素碳水化合物组与Slit和Robo的相互作用和生物活性不同。肝素/硫酸乙酰肝素（HS）糖胺聚糖是Slit-Robo细胞应答所必需的。有证据表明Slit、Robo和肝素/HS的每种组合之间存在相互作用，并形成三元复合物。肝素/HS是复杂的混合物，显示出广泛的结构多样性。这种多样性的相关性已经在有限的程度上进行了研究，使用一些选择的化学修饰的肝素作为模型的HS多样性。在这里，我们扩展这些研究的平行筛选的结构不同的面板8化学修饰的肝素多糖和众多的天然HS寡糖色谱馏分结合果蝇狭缝和机器人N-末端结构域和激活小鸡视网膜轴突响应狭缝片段。多糖和低聚糖组分都显示结合和细胞活性的变异性，这不能仅仅归因于增加硫酸化，延长了天然HS以及模型改性肝素结构多样性重要性的证据。与Robo相比，它们与Slit的相互作用也存在差异，Robo更喜欢硫酸化程度较高的化合物。此外，化合物之间的细胞活性模式与结合每种蛋白质的细胞活性模式不同，这表明生物学结果是以一种微妙的方式选择性确定的，而不是简单地反映肝素/HS与Slit和Robo的单独相互作用的总和。
Panels of heparin/heparan sulfate carbohydrates differ in their interactions and bioactivity with Slit and Robo. Heparin/heparan sulfate (HS) glycosaminoglycans are required for Slit–Robo cellular responses. Evidence exists for interactions between each combination of Slit, Robo and heparin/HS and for formation of a ternary complex. Heparin/HS are complex mixtures displaying extensive structural diversity. The relevance of this diversity has been studied to a limited extent using a few select chemically-modified heparins as models of HS diversity. Here we extend these studies by parallel screening of structurally diverse panels of eight chemically-modified heparin polysaccharides and numerous natural HS oligosaccharide chromatographic fractions for binding to both Drosophila Slit and Robo N-terminal domains and for activation of a chick retina axon response to the Slit fragment. Both the polysaccharides and oligosaccharide fractions displayed variability in binding and cellular activity that could not be attributed solely to increasing sulfation, extending evidence for the importance of structural diversity to natural HS as well as model modified heparins. They also displayed differences in their interactions with Slit compared to Robo, with Robo preferring compounds with higher sulfation. Furthermore, the patterns of cellular activity across compounds were different to those for binding to each protein, suggesting that biological outcomes are selectively determined in a subtle manner that does not simply reflect the sum of the separate interactions of heparin/HS with Slit and Robo.
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DOI：
10.1074/jbc.m800688200
发表时间：
2008-06-06
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Fukuhara N;Howitt JA;Hussain SA;Hohenester E
通讯作者：
Hohenester E
影响因子：
64.5
作者：
Brose, K;Bland, KS;Kidd, T
通讯作者：
Kidd, T
影响因子：
5.3
作者：
Milligan, ED;O'Connor, KA;Watkins, LR
通讯作者：
Watkins, LR
影响因子：
2.9
作者：
LINHARDT, RJ;TURNBULL, JE;GALLAGHER, JT
通讯作者：
GALLAGHER, JT
影响因子：
64.5
作者：
Kidd, T;Bland, KS;Goodman, CS
通讯作者：
Goodman, CS