Enhanced self-association of mucins possessing the T and Tn carbohydrate cancer antigens at the single-molecule level.
Enhanced self-association of mucins possessing the T and Tn carbohydrate cancer antigens at the single-molecule level.
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DOI：
10.1021/bm300135h
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发表时间：
2012-05-14
影响因子：
6.2
通讯作者：
Sletmoen, Marit
中科院分区：
文献类型：
--
作者：
Haugstad, Kristin E.;Gerken, Thomas A.;Stokke, Bjorn T.;Dam, Tarun K.;Brewer, C. Fred;Sletmoen, Marit
粘蛋白是线性 O-糖基化糖蛋白，参与炎症、细胞粘附和肿瘤发生。癌症相关粘蛋白通常具有 T (Galβ1,3GalNAcαThr/Ser) 和 Tn (GalNAcαThr/Ser) 癌症抗原表达增加，这些抗原是包括结肠癌在内的多种癌症的诊断标志物。我们在接近生理条件下使用基于 AFM 的单分子强制解离来研究猪颌下粘蛋白 (PSM) 之间以及具有各种碳水化合物（包括 T 和 Tn 抗原）的 PSM 类似物之间的自相互作用。确定了从 0.18 nN/s 到 39 nN/s 的力加载速率的解绑力和相应的力加载速率的分布，并进行处理以产生最可能的解绑力 f* 和相互作用的寿命。各种粘蛋白在力加载速率约为 2 nN/s 时，参数 f* 在 27 至 50 pN 范围内变化。研究的所有粘蛋白样品均显示出自相互作用，但仅显示 Tn 抗原 (Tn-PSM) 或 Tn-、T-抗原和三糖 Fucα1,2Galβ1,3GalNAc (Tri-PSM) 的混合物的 PSM 的趋势最大。观察到天然 PSM (Fd-PSM) 的自相互作用较弱，其由较长的核心 1 血型 A 四糖 (GalNAcα1,3(Fucα1,2)Galβ1,3GalNAcαSer/Thr) 和 Tn 抗原的几乎相等的混合物组成。该数据与增强粘蛋白自相互作用的截短 Tn 和 T 聚糖一致。因此，这些碳水化合物癌抗原可能通过细胞上的自缔合而组成型激活粘蛋白和粘蛋白型受体，从而在疾病中发挥积极作用。
Mucins are linear O-glycosylated glycoproteins involved in inflammation, cell adhesion and tumorigenesis. Cancer associated mucins often possess increased expression of the T (Galβ1,3GalNAcαThr/Ser) and Tn (GalNAcαThr/Ser) cancer antigens, which are diagnotic markers for several cancers including colon cancer. We have used AFM based single-molecule forced unbinding under near physiological conditions to investigate the self-interactions between porcine submaxillary mucin (PSM) as well as between PSM analogs possessing various carbohydrates including the T- and Tn-antigen. Distributions of unbinding forces and corresponding force loading rates were determined for force loading rates from 0.18 nN/s to 39 nN/s, and processed to yield most probable unbinding forces f* and lifetimes of the interactions. Parameter f* varied in the range 27 to 50 pN at force loading rates of about 2 nN/s among the various mucins. All mucin samples investigated showed self-interaction, but the tendency was greatest for PSM displaying only the Tn-antigen (Tn-PSM) or a mixture of Tn-, T-antigen and the trisaccharide Fucα1,2Galβ1,3GalNAc (Tri-PSM). Weaker self-interactions were observed for native PSM (Fd-PSM), which consists of a nearly equal mixture of the longer core 1 blood group A tetrasaccharide (GalNAcα1,3(Fucα1,2)Galβ1,3GalNAcαSer/Thr) and Tn-antigen. The data are consistent with the truncated Tn and T glycans enhancing self-interaction of the mucins. These carbohydrate cancer antigens may thus play an active role in the disease by constitutively activating mucin and mucin-type receptors by self-association on cells.
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DOI：
10.1073/pnas.0806085105
发表时间：
2008-10-14
影响因子：
11.1
作者：
Dudko, Olga K.;Hummer, Gerhard;Szabo, Attila
通讯作者：
Szabo, Attila
影响因子：
2.9
作者：
GERKEN, TA;BUTENHOF, KJ;SHOGREN, R
通讯作者：
SHOGREN, R
影响因子：
4.8
作者：
Gerken, TA;Gilmore, M;Zhang, JX
通讯作者：
Zhang, JX
影响因子：
3.4
作者：
Evans, E;Ritchie, K
通讯作者：
Ritchie, K
影响因子：
3
作者：
Hakomori, S
通讯作者：
Hakomori, S