Galectin multimerization and lattice formation are regulated by linker region structure
Galectin multimerization and lattice formation are regulated by linker region structure
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DOI：
10.1093/glycob/cwq144
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发表时间：
2011-01-01
期刊：
影响因子：
4.3
通讯作者：
Baum, Linda G.
中科院分区：
文献类型：
--
作者：
Earl, Lesley A.;Bi, Shuguang;Baum, Linda G.
半乳糖凝集素通过与细胞表面糖蛋白受体上的聚糖配体结合来调节细胞功能。原型半乳糖凝集素，如半乳糖凝集素-1，是一种非共价二聚化的碳水化合物识别结构域（CRD）单体，而串联重复半乳糖凝集素，如半乳糖凝集素-9，具有两个通过接头结构域连接的不相同的CRD。原型半乳糖凝集素或串联重复半乳糖凝集素中的两种CRD的二聚化通常是糖蛋白受体交联和随后的细胞信号传导所需的。几项研究已经发现，串联重复半乳糖凝集素在触发许多细胞应答（包括细胞死亡）方面比原型半乳糖凝集素更有效。这些差异可能是由于CRD特异性、CRD之间接头结构域的存在或不存在或两者所致。为了询问串联重复半乳糖凝集素与原型半乳糖凝集素相比在触发细胞死亡方面增加的效力的基础，我们创建了三个串联重复半乳糖凝集素构建体，其具有连接相同半乳糖凝集素-1 CRD的不同接头区域，使得我们观察到的任何差异将是由于接头区域的贡献而不是由于CRD特异性。我们发现，允许两个半乳糖凝集素-1 CRD分离的无规卷曲或刚性α-螺旋接头促进了高阶半乳糖凝集素多聚体的形成，并且与天然半乳糖凝集素-1或具有短刚性接头的构建体相比，这些半乳糖凝集素在与聚糖配体和细胞表面糖蛋白受体结合以及触发T细胞死亡方面更有效。因此，与原型半乳糖凝集素相比，串联重复半乳糖凝集素的增加的效力可能是由于接头结构域允许分子间CRD相互作用的能力，导致形成具有增加的化合价的高阶多聚体，而不是CRD特异性的差异。
Galectins regulate cellular functions by binding to glycan ligands on cell surface glycoprotein receptors. Prototype galectins, such as galectin-1, are one carbohydrate recognition domain (CRD) monomers that noncovalently dimerize, whereas tandem-repeat galectins, such as galectin-9, have two non-identical CRDs connected by a linker domain. Dimerization of prototype galectins, or both CRDs in tandem-repeat galectins, is typically required for the crosslinking of glycoprotein receptors and subsequent cellular signaling. Several studies have found that tandem-repeat galectins are more potent than prototype galectins in triggering many cell responses, including cell death. These differences could be due to CRD specificity, the presence or absence of a linker domain between CRDs, or both. To interrogate the basis for the increased potency of tandem-repeat galectins compared with prototype galectins in triggering cell death, we created three tandem-repeat galectin constructs with different linker regions joining identical galectin-1 CRDs, so that any differences we observed would be due to the contribution of the linker region rather than due to CRD specificity. We found that random-coil or rigid a-helical linkers that permit separation of the two galectin-1 CRDs facilitated the formation of higher-order galectin multimers and that these galectins were more potent in binding to glycan ligands and cell surface glycoprotein receptors, as well as triggering T cell death, compared with native galectin-1 or a construct with a short rigid linker. Thus, the increased potency of tandem-repeat galectins compared with prototype galectins is likely due to the ability of the linker domain to permit intermolecular CRD interactions, resulting in the formation of higher-order multimers with increased valency, rather than differences in CRD specificity.