Molecular diversity of heparan sulfate
Molecular diversity of heparan sulfate
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DOI：
10.1172/jci200113530
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发表时间：
2001-07-01
影响因子：
15.9
通讯作者：
Lindahl, U
中科院分区：
文献类型：
--
作者：
Esko, JD;Lindahl, U
J. Clin. Invest. 108：169-173（2001）。DOI：10.1172/JCI 200113530。二糖组成的术语;所述二糖的区别在于存在硫酸化或非硫酸化的GlcA/IdoA和GlcN残基。一般来说，同一组二糖存在于大多数组织中，但它们的相对含量在数量上有所不同。例如，二糖GlcA-GlcNS 3S主要存在于内皮细胞和结缔组织肥大细胞中，因为该单元是结合抗凝血酶的五糖序列中的关键子结构（13，14）。相比之下，肾脏HS含有大量IdoA 2SGlcNS 3S，但该单位在配体结合中的精确功能尚不清楚（15）。有趣的是，HS的基本结构二糖似乎是相当古老的。另一种表征结构的方法是根据GlcN残基的主要N-取代基的相对分布：连续的N-乙酰化二糖单元（NA结构域），连续的可变长度的N-硫酸化序列（NS结构域），以及交替的N-乙酰化和N-硫酸化单元（NA/NS结构域）（图1）。这种N-取代模式似乎是从中获得HS的细胞/组织的特征。值得注意的是，肝素，肥大细胞多糖，可以被认为是基本上是一个单一的，不寻常的扩展NS域。由于其他修饰，如GlcA的O-硫酸化和差向异构化为L-IdoA，取决于GlcN单元的先前N-硫酸化，因此修饰的二糖单元倾向于聚集在NS或NA/NS结构域中（16）。二糖组成和NA和NS结构域的排列本身并不限定特异性配体的结合位点。相反，结合发生在通常在NS或NA/NS结构域内的特定的经修饰的二糖组（17，18）。迄今为止研究最多的例子是HS/肝素和抗凝血酶之间的“锁和钥匙”相互作用，这导致凝血级联中凝血酶、因子Xa和其他丝氨酸蛋白酶的失活。这种相互作用取决于含有中心3-O-硫酸化GlcN残基（Glc-NAc 6SGlcAGlcNS 3S 6SIdoA 2SGlcNS 6S）的五糖的非常特定的结构（参见图1，底部）（13）。其他例子是来自单纯疱疹病毒的糖蛋白gD（参见Shukla和Spear，本透视系列，参考文献19）与含有IdoA 2S-GlcN 3S的寡糖的相互作用，以及FGF-1和FGF-2与含有不同组合的IdoA 2S和GlcN 6S单元的N-硫酸化五糖序列的相互作用（参见Gallagher，本系列，参考文献20;和参考文献21）。其他配体及其相应寡糖序列的结合位点的分布不太清楚。最近的研究集中在介导PDGF、血小板因子4、HGF（分散因子）、脂蛋白脂肪酶、单纯疱疹糖蛋白gC、层粘连蛋白和趋化因子的结合和/或活化的序列上。一些结合位点涉及链的不连续结构域（例如，IFN-γ、血小板因子4和IL-8）（相关参考文献见参考文献16）。在其他情况下，该链可以充当模板，使配体与其结合配偶体近似（13，22，23）。结合位点的表达以组织特异性方式发生，并且可以在发育、衰老和疾病期间发生变化。一个尚未探索的问题涉及同一物种的不同个体中给定组织的结构的潜在变化，这可能是由营养或遗传背景的差异引起的。
J. Clin. Invest. 108: 169–173 (2001). DOI: 10.1172/JCI200113530. terms of disaccharide composition; the disaccharides are distinguished by the presence of variably sulfated or nonsulfated GlcA/IdoA and GlcN residues. Generally, the same set of disaccharides exists in most tissues, but their relative content varies quantitatively. For example, the disaccharide GlcA-GlcNS3S occurs predominantly in endothelial cells and connective tissue mast cells, as this unit is a critical substructure in the pentasaccharide sequence that binds antithrombin (13, 14). In contrast, kidney HS contains a large amount of IdoA2SGlcNS3S, but the precise function of this unit in ligand binding is not known (15). Interestingly, the basic structural disaccharides of HS appear to be quite ancient.Another way to characterize structure is in terms of the relative distribution of the major N-substituents of the GlcN residues: tracts of contiguous N-acetylated disaccharide units (NA domains), contiguous N-sulfated sequences of variable length (NS domains), and alternating N-acetylated and N-sulfated units (NA/NS domains)(Figure 1). Such N-substitution patterns appear to be characteristic of the cells/tissues from which the HS was obtained. Notably, heparin, the mast cell polysaccharide, may be considered essentially a single, unusually extended NS domain. Since other modifications, such as O-sulfation and epimerization of GlcA to L-IdoA, depend on prior N-sulfation of GlcN units, the modified disaccharide units tend to cluster in the NS or NA/NS domains (16). The disaccharide composition and the arrangement of NA and NS domains do not by themselves define binding sites for specific ligands. Instead, binding occurs to specific sets of variably modified disaccharides usually within the NS or NA/NS domains (17, 18). The beststudied example to date is the “lock-and-key” interaction between HS/heparin and antithrombin, which leads to inactivation of thrombin, factor Xa, and other serine proteinases of the coagulation cascade. This interaction depends on a very specific structure of a pentasaccharide that contains a central 3-O-sulfated GlcN residue (Glc-NAc6SGlcAGlcNS3S6SIdoA2SGlcNS6S)(see Figure 1, bottom)(13). Other examples are the interactions of glycoprotein gD from Herpes simplex virus (see Shukla and Spear, this Perspective series, ref. 19) with an oligosaccharide containing IdoA2S-GlcN3S and of FGF-1 and FGF-2 with N-sulfated pentasaccharide sequences containing IdoA2S and GlcN6S units in distinct combinations (see Gallagher, this series, ref. 20; and ref. 21). The distribution of binding sites for other ligands and their corresponding oligosaccharide sequences are less clearcut. Recent studies have focused on sequences that mediate binding and/or activation of PDGF, platelet factor 4, HGF (scatter factor), lipoprotein lipase, Herpes simplex glycoprotein gC, laminin, and chemokines. Some of the binding sites involve discontinuous domains of the chains (eg, IFN-γ, platelet factor 4, and IL-8)(see ref. 16 for relevant references). In other cases, the chain may act as a template, approximating a ligand with its binding partner (13, 22, 23). The expression of binding sites occurs in a tissue-specific manner and can change during development, aging, and disease. An unexplored question concerns the potential variation of structure in a given tissue in different individuals of the same species that might arise from differences in nutrition or genetic background.