Conformational degeneracy restricts the effective information content of heparan sulfate
Conformational degeneracy restricts the effective information content of heparan sulfate
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DOI：
10.1039/b923519a
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发表时间：
2010-05-01
影响因子：
--
通讯作者：
Yates, Edwin A.
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文献类型：
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作者：
Rudd, Timothy R.;Yates, Edwin A.
线性硫酸化多糖硫酸乙酰肝素在细胞间信号转导事件中占据关键地位，与细胞表面和细胞外基质中的众多蛋白质相互作用。其复杂的序列表明具有很高的潜在信息含量，但尽管付出了广泛的努力，其取代模式和生物活性之间的明确关系仍然难以捉摸。这是由于技术限制造成的，再加上试图将取代模式与活性直接关联而不考虑其他构象因素。对于一系列系统修饰的硫酸乙酰肝素类似物，通过化学计量分析探索了取代模式与实验 C-13 NMR 化学位移之间的关系，C-13 NMR 化学位移充当构象变化存在的报告者，特别是在糖苷键周围。从实验数据分析可以明显看出，艾杜糖醛酸中的O-硫酸化和葡萄糖胺残基中的N-硫酸化引起了广泛的连锁变异，但它们的影响是不同的，而6-O-硫酸化的影响要小得多。糖序列模型表明，糖苷键变异的最大传播发生在最大序列多样性之前，并揭示了一个高度简并的系统：一小部分可能的序列足以提供不同的主链构象，以满足特定的蛋白质结合要求。 HS 序列中潜在可用的独特信息内容（最终由构象定义）远远低于潜在的序列多样性。
The linear, sulfated polysaccharide heparan sulfate occupies a pivotal position in intercellular signalling events, interacting with numerous proteins on the cell surface and in the extracellular matrix. Its complex sequences suggest high potential information content but, despite extensive efforts, a clear relationship between its substitution pattern and biological activity remains elusive. This results from technical limitations, compounded by attempts to correlate substitution pattern directly with activity without considering other conformational factors. For a series of systematically modified analogues of heparan sulfate, the relationship between substitution pattern and experimental C-13 NMR chemical shifts, which act as reporters of the presence of conformational change, particularly around the glycosidic linkages, was explored through chemometric analysis. From analysis of the experimental data it was evident that wide linkage variation arose from O-sulfation in iduronate and N-sulfation in glucosamine residues but, their effects were distinct, while 6-O-sulfation had much less impact. Models of saccharide sequences showed that the maximum spread of variation in glycosidic linkages occurred before maximum sequence diversity and revealed a highly degenerate system: a fraction of possible sequences is sufficient to provide diverse backbone conformations to satisfy particular protein binding requirements. The unique information content potentially available in HS sequences, defined ultimately by conformation, is vastly inferior to the potential sequence diversity.