Structural insights into the recognition mechanism between an antitumor galectin AAL and the Thomsen-Friedenreich antigen
Structural insights into the recognition mechanism between an antitumor galectin AAL and the Thomsen-Friedenreich antigen
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DOI：
10.1096/fj.10-159111
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发表时间：
2010-10-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Da-Cheng
中科院分区：
文献类型：
--
作者：
Feng, Lei;Sun, Hui;Wang, Da-Cheng
在调节癌细胞增殖中起重要作用的TF抗原在所有人类癌症和癌前病症的90%中发生。虽然TF抗原作为一种泛癌抗原已被发现近80年，但TF抗原与靶蛋白之间的识别机制尚未被结构表征。大量研究表明TF二糖是半乳糖苷结合半乳糖凝集素的潜在配体。在这项工作中，我们确定了TF抗原作为一个潜在的配体的抗肿瘤半乳糖凝集素AAL（茶树菇凝集素）通过聚糖阵列分析，并报告的晶体结构的AAL与TF抗原复合。该结构提供了AAL和TF抗原之间的识别模式的第一个外观，这是独特的保守的（谷氨酸-水-精氨酸-水）的结构基序为基础的氢键网络。基于结构的诱变分析进一步揭示了负责识别特异性和结合亲和力的残基。AAL与另外两种含TF的聚糖复合的晶体结构表明，独特的TF识别模式保持完整，这可能在一些癌症相关的半乳糖凝集素中普遍采用。这一发现为以AAL-TF识别模式为原型的抗肿瘤药物设计及相关策略提供了新的靶点和途径。冯，L.，孙，H.，张玉，李，D.- F.、王维，D.- C.抗肿瘤半乳糖凝集素AAL和B-F抗原之间的识别机制的结构见解。FASEB J.24，3861-3868（2010）。www.fasebj.org
Thomsen-Friedenreich (TF) antigen, which plays an important role in the regulation of cancer cell proliferation, occurs in similar to 90% of all human cancers and precancerous conditions. Although TF antigen has been known for almost 80 yr as a pancarcinoma antigen, the recognition mechanism between TF antigen and target protein has not been structurally characterized. A number of studies indicated that TF disaccharide is a potential ligand of the galactoside-binding galectins. In this work, we identified the TF antigen as a potential ligand of the antitumor galectin AAL (Agrocybe aegerita lectin) through glycan array analysis and reported the crystal structure of AAL complexed with the TF antigen. The structure provides a first look at the recognition mode between AAL and TF antigen, which is unique in a conservative (Glu-water-Arg-water) structural motif-based hydrogen bond network. Structure-based mutagenesis analysis further revealed the residues responsible for recognition specificity and binding affinity. Crystal structures of AAL complexed with two other TF-containing glycans showed that the unique TF recognition mode is kept intact, which may be commonly adopted in some cancer-related galectins. The finding provided the new target and approach for the antitumor drug design and relative strategy based on the AAL-TF recognition mode as a prototype model.-Feng, L., Sun, H., Zhang, Y., Li, D.-F., Wang, D.-C. Structural insights into the recognition mechanism between an antitumor galectin AAL and the Thomsen-Friedenreich antigen. FASEB J. 24, 3861-3868 (2010). www.fasebj.org