Terminal sialic acids on CD44 N-glycans can block hyaluronan binding by forming competing intramolecular contacts with arginine sidechains.
Terminal sialic acids on CD44 N-glycans can block hyaluronan binding by forming competing intramolecular contacts with arginine sidechains.
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DOI：
10.1002/prot.24668
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发表时间：
2014-11
影响因子：
2.9
通讯作者：
Guvench, Olgun
中科院分区：
文献类型：
--
作者：
Faller, Christina E.;Guvench, Olgun
特定的糖残基及其连接形成了糖蛋白与其他生物分子相互作用的分子识别基础。看似微小的变化，如在糖蛋白的共价连接的聚糖组分中添加单个单糖，可以极大地影响这些相互作用。例如，聚糖的唾液酸加帽影响参与细胞-细胞和细胞-基质相互作用的蛋白质-配体结合。CD 44是一种单通道跨膜糖蛋白，其与其碳水化合物配体透明质酸（HA）（细胞外基质组分）结合，介导白细胞归巢、细胞粘附和肿瘤转移等过程。这种结合受到N-末端细胞外透明质酸结合结构域（HABD）糖基化的高度调节;具体而言，HABD的唾液酸加帽N-聚糖抑制配体结合。然而，这种唾液酸介导的调节背后的分子机制仍然未知。HABD的五个N-糖基化位点中的两个先前已被鉴定为对HA结合具有最大的抑制作用，但仅当聚糖含有末端唾液酸残基时。在本研究中，选择这两个位点Asn 25和Asn 120进行计算机模拟糖基化。在这里，从广泛的标准分子动力学模拟和有偏见的模拟，我们提出了一个分子机制，这种行为的基础上自发形成的电荷配对的氢键之间的相互作用带负电荷的唾液酸残基和带正电荷的精氨酸侧链已知是至关重要的结合到HA，这本身是带负电荷的。这样的分子内氢键将排除对透明质酸结合至关重要的缔合。这一观察结果表明，CD 44和相关糖蛋白结合是如何调节唾液酸化细胞环境波动。
Specific sugar residues and their linkages form the basis of molecular recognition for interactions of glycoproteins with other biomolecules. Seemingly small changes, like the addition of a single monosaccharide in the covalently attached glycan component of glycoproteins, can greatly affect these interactions. For instance, the sialic acid capping of glycans affects protein-ligand binding involved in cell-cell and cell-matrix interactions. CD44 is a single-pass transmembrane glycoprotein whose binding with its carbohydrate ligand hyaluronan (HA), an extracellular matrix component, mediates processes such as leukocyte homing, cell adhesion, and tumor metastasis. This binding is highly regulated by glycosylation of the N-terminal extracellular hyaluronan-binding domain (HABD); specifically, sialic acid capped N-glycans of HABD inhibit ligand binding. However, the molecular mechanism behind this sialic acid mediated regulation has remained unknown. Two of the five N-glycosyation sites of HABD have been previously identified as having the greatest inhibitory effect on HA binding, but only if the glycans contain terminal sialic acid residues. These two sites, Asn25 and Asn120, were chosen for in silico glycosylation in this study. Here, from extensive standard molecular dynamics simulations and biased simulations, we propose a molecular mechanism for this behavior based on spontaneously-formed charge-paired hydrogen bonding interactions between the negatively-charged sialic acid residues and positively-charged Arg sidechains known to be critically important for binding to HA, which itself is negatively charged. Such intramolecular hydrogen bonds would preclude associations critical to hyaluronan binding. This observation suggests how CD44 and related glycoprotein binding is regulated by sialylation as cellular environments fluctuate.
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DOI：
10.1083/jcb.128.4.673
发表时间：
1995-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jackson DG;Bell JI;Dickinson R;Timans J;Shields J;Whittle N
通讯作者：
Whittle N
影响因子：
16.8
作者：
Banerji, Suneale;Wright, Alan J.;Jackson, David G.
通讯作者：
Jackson, David G.
影响因子：
5.5
作者：
Guvench, Olgun;Hatcher, Elizabeth;Venable, Richard M.;Pastor, Richard W.;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M