Molecular diversity of heparan sulfate
Molecular diversity of heparan sulfate
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DOI：
10.1172/jci13530
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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·克莱恩。投资。108：169-173(2001)。DOI：10.1172/JCI200113530。二糖组成的术语；二糖的区别在于存在可变的硫化或非硫化的Glca/IoA和GlcN残基。通常情况下，大多数组织中都存在相同的一组双糖，但它们的相对含量在数量上有所不同。例如，二糖Glca-GlcNS3S主要存在于内皮细胞和结缔组织肥大细胞中，因为这个单位是结合抗凝血酶(13，14)的五糖序列中的一个关键亚结构。相反，肾脏HS含有大量的IdoA2SGlcNS3S，但该单位在配体结合中的确切功能尚不清楚(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域)，连续的可变长度的N-硫化序列(NS域)，以及交替的N-乙酰化和N-硫化单元(NA/NS域)(图1)。这种N-取代模式似乎是获得HS的细胞/组织的特征。值得注意的是，肝素，肥大细胞多糖，可以被认为基本上是一个单一的，异常扩展的NS结构域。由于其他修饰，如GLCA的O-硫化和L-IOA的异构化，依赖于GlcN单元先前的N-硫化，所以修饰的双糖单元倾向于聚集在NS或NA/NS结构域(16)中。双糖的组成和NA和NS结构域的排列本身并不定义特定配体的结合位置。相反，通常在NS或NA/NS结构域(17，18)内与特定的可变修饰双糖结合。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，这种作用导致凝血酶、凝血因子Xa和凝血级联反应中的其他丝氨酸蛋白酶失活。这种相互作用取决于含有中心3-O-磺化GlcN残基的五糖的非常特殊的结构(GLC-NAc6SGlcAGlcNS3S6SIdoA2SGlcNS6S)(见图1，底部)(13)。其他例子是来自单纯疱疹病毒的糖蛋白gD的相互作用(见Shukla和Spear，This透视系列，参考文献。19)含有IdoA2S-GlcN3S的低聚糖，以及含有不同组合中的IdoA2S和GlcN6S单元的N-硫酸化五糖序列的成纤维细胞生长因子-1和成纤维细胞生长因子-2(见Gallagher，本系列，参考文献)。20；和参考21)。其他配体及其对应的寡糖序列的结合位点分布不太明确。最近的研究集中在介导PDGF、血小板因子4、HGF(散布因子)、脂蛋白脂肪酶、单纯疱疹病毒糖蛋白GC、层粘连蛋白和趋化因子结合和/或激活的序列。一些结合位点涉及链的不连续结构域(例如，干扰素-γ、血小板因子4和IL-8)(见参考文献。16以供参考)。在其他情况下，链可以作为模板，与配体及其结合伙伴(13、22、23)近似。结合位点的表达是以组织特有的方式发生的，在发育、衰老和疾病过程中可以改变。一个未探索的问题涉及同一物种的不同个体在给定组织中的结构可能由于营养或遗传背景的差异而产生的潜在变化。
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.