Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries.
Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries.
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DOI：
10.3109/03008207.2015.1045066
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发表时间：
2015
影响因子：
2.9
通讯作者：
Pacifici M
中科院分区：
文献类型：
--
作者：
Billings PC;Pacifici M
硫酸乙酰肝素(HS)是细胞表面和基质相关蛋白多糖(HSPGs)的组成部分，它们共同在细胞分化、器官形态发生和癌症等许多生理过程中发挥重要作用。HS的一个关键功能是与信号蛋白、生长因子、血浆蛋白、免疫调节剂和其他因子结合和相互作用。在这样做的过程中，HS链和HSPG能够调节蛋白质的分布、生物利用度和对靶细胞的作用，也可以作为细胞表面的辅助受体，促进配体-受体的相互作用。这些蛋白含有HS/肝素结合域(HBD)，该结构域介导它们与HS的结合和接触。HBD在序列和预测的结构上高度多样化，包含碱性氨基酸(Lys，Arg)簇，并具有整体净正电荷，最常见的是在共识的Cardin-WeIntraub(CW)基序中。有趣的是，现在已知其他结构域和残基也会影响蛋白质-HS的相互作用，以及与其他糖胺聚糖的相互作用，如硫酸软骨素。在这篇综述中，我们描述和分析了蛋白质中的HBD，包括双调节蛋白、成纤维细胞生长因子家族成员、肝素酶、硬化素和刺猬蛋白家族成员。我们讨论了HBD的结构和功能特征以及其他蛋白质结构域所发挥的重要作用，并对Sonic、印度和沙漠刺猬中存在的CW基序的多样性提供了新的构象见解。最后，我们综述了一种罕见的儿童骨骼疾病-遗传性多发性外生性骨病(HME)的发病机制的研究进展，该疾病的特征是HS缺乏和软骨肿瘤形成。了解蛋白质-HS相互作用的进展将对基础生物学和转化医学以及基于HS的治疗学的发展具有广泛的意义。
Heparan sulfate (HS) is a component of cell surface and matrix-associated proteoglycans (HSPGs) that collectively, play crucial roles in many physiologic processes including cell differentiation, organ morphogenesis and cancer. A key function of HS is to bind and interact with signaling proteins, growth factors, plasma proteins, immune-modulators and other factors. In so doing, the HS chains and HSPGs are able to regulate protein distribution, bio-availability and action on target cells and can also serve as cell surface co-receptors, facilitating ligand-receptor interactions. These proteins contain an HS/heparin-binding domain (HBD) that mediates their association and contacts with HS. HBDs are highly diverse in sequence and predicted structure, contain clusters of basic amino acids (Lys, Arg) and possess an overall net positive charge, most often within a consensus Cardin-Weintraub (CW) motif. Interestingly, other domains and residues are now known to influence protein-HS interactions, as well as interactions with other glycosaminoglycans, such as chondroitin sulfate. In this review we provide a description and analysis of HBDs in proteins including amphiregulin, fibroblast growth factor family members, heparanase, sclerostin and hedgehog protein family members. We discuss HBD structural and functional features and important roles carried out by other protein domains, and also provide novel conformational insights into the diversity of CW motifs present in Sonic, Indian and Desert hedgehogs. Finally, we review progress in understanding the pathogenesis of a rare pediatric skeletal disorder, Hereditary Multiple Exostoses (HME), characterized by HS deficiency and cartilage tumor formation. Advances in understanding protein-HS interactions will have broad implications for basic biology and translational medicine as well as for the development of HS-based therapeutics.