Following sugar patterns in search of galectin function.
Following sugar patterns in search of galectin function.
复制标题
遵循糖模式寻找半乳糖凝集素功能。
DOI：
10.1073/pnas.1801039115
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发表时间：
2018
影响因子：
11.1
通讯作者：
Godula,Kamil
中科院分区：
文献类型：
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作者：
Godula,Kamil
通过进化，聚糖被选为一类生物分子，其任务是促进细胞边界的信息交换（1）。聚糖作为膜蛋白上的附着物或直接连接到嵌入细胞质膜中的脂质，作为聚糖结合蛋白（如凝集素或抗体）的识别元件，并介导基本的生物学过程，从细胞-细胞粘附和迁移到与生物体发育和功能相关的更复杂的事件。毫不奇怪，聚糖也有助于疾病的发生和进展，并且与大量病理生理过程有关，包括传染病、癌症或自身免疫性疾病（2）。然而，聚糖及其同源凝集素反受体仍然很少被认为是合适的药物靶标（3）。(4)采用细胞表面模拟模型来剖析细胞膜中的聚糖受体组织如何影响与半乳糖凝集素（一种人类凝集素家族）的功能关联（5）。在它们的许多功能中，半乳糖凝集素已被鉴定为免疫应答的重要细胞外调节剂，并且与肿瘤的侵袭性增加正相关（6）。因此，半乳糖凝集素肯定是医疗干预的诱人目标（7）;然而，对于半乳糖凝集素家族成员观察到的广泛功能多态性需要首先建立管理其与聚糖受体相互作用的原则，以指导选择性半乳糖凝集素靶向治疗剂的设计。聚糖的结构决定了其与凝集素的分子相互作用，半乳糖凝集素家族的所有成员通常识别含有β-半乳糖残基的聚糖（8），修饰如唾液酸化（9）或硫酸化（10）提供附加亲和力。对于大多数凝集素来说，半乳糖凝集素对简单的可溶性β-半乳糖苷如乳糖显示出弱的（高微摩尔至低毫摩尔）亲和力。在生物环境中观察到的半乳糖凝集素的高得多的亲和力相互作用（亚微摩尔）是其以多价方式在细胞表面和细胞外基质中接合聚糖集合体的能力的结果（11）。这种聚糖特有的行为称为“糖苷簇效应”（12），提供了一种增强凝集素识别聚糖的总体亲和力和选择性的机制，同时还能够设定触发信号传导反应的阈值。因此，不仅可以通过改变聚糖的结构，还可以通过改变细胞糖萼内聚糖决定簇的密度和空间组织来实现调节生物学功能（13）。聚糖在细胞表面上的多价呈递反映在凝集素的结构中，凝集素通常被组织成呈递几个聚糖识别结构域（CRD）。对于半乳糖凝集素也是如此，根据其CRD的组织，半乳糖凝集素可以分为三个不同的组，即原型、嵌合和串联重复（图1）（8）。的
Through evolution, glycans have been selected as a class of biomolecules tasked with facilitating information exchange at the cellular boundary (1). Presented as attachments on membrane proteins or linked directly to lipids embedded in the plasma membrane of cells, glycans serve as recognition elements for glycan binding proteins, such as lectins or antibodies, and mediate essential biological processes, ranging from cell–cell adhesion and migration to more complex events associated with organismal development and function. Not surprisingly, glycans also contribute to disease development and progression and have been linked to a large number of pathophysiological processes, including infectious diseases, cancer, or autoimmune disorders (2). However, glycans and their cognate lectin counter-receptors are still rarely considered as suitable drug targets (3).In PNAS, Xiao et al.(4) employ cell-surface mimetic models to dissect how glycan receptor organization in cellular membranes influences functional association with galectins, a family of human lectins (5). Among their many functions, galectins have been identified to serve as important extracellular modulators of immune responses and have been positively correlated with increased aggressiveness of tumors (6). As such, galectins are certainly enticing targets for medical intervention (7); however, the broad functional polymorphism observed for the galectin family members necessitates that principles governing their interactions with glycan receptors be established first to guide the design of selective galectin-targeting therapeutics. The structures of glycans define their molecular interactions with lectins and all members of the galectin family generally recognize glycans containing β-galactose residues (8), with modifications such as sialylation (9) or sulfation (10) providing addition affinity. As is typical for most lectins, galectins show weak (high micromolar to low millimolar) affinity for simple soluble β-galactosides, such as lactose. The much higher-affinity interactions (submicromolar) observed for galectins in biological settings are the result of their ability to engage ensembles of glycans at surfaces of cells and in the extracellular matrix in a multivalent fashion (11). This behavior, characteristic to glycans and referred to as the “glycoside cluster effect”(12), provides a mechanism for enhancing the overall affinity and selectivity of glycan recognition by lectins, while also enabling the setting of thresholds for triggering signaling responses. Modulating biological functions can thus be achieved not only by altering the structures of glycans but also by varying the density and spatial organization of glycan determinants within the cellular glycocalyx (13). The multivalent presentation of glycans on surfaces of cells is mirrored in the architecture of lectins, which are often organized to present several glycan recognition domains (CRDs). This is also true for galectins, which can be classified into three distinct groups, according to the organization of their CRDs, as prototypical, chimeric, and tandem-repeat (Fig. 1)(8). The