Structural Basis of Tumor Suppressor in Lung Cancer 1 (TSLC1) Binding to Differentially Expressed in Adenocarcinoma of the Lung (DAL-1/4.1B)
Structural Basis of Tumor Suppressor in Lung Cancer 1 (TSLC1) Binding to Differentially Expressed in Adenocarcinoma of the Lung (DAL-1/4.1B)
复制标题
DOI：
10.1074/jbc.m110.174011
复制
发表时间：
2011-02-01
影响因子：
4.8
通讯作者：
Hallberg, B. Martin
中科院分区：
文献类型：
--
作者：
Busam, Robert D.;Thorsell, Ann-Gerd;Hallberg, B. Martin
受干扰的细胞粘附机制是肿瘤侵袭和转移的关键。细胞粘附蛋白TSLC1（肺癌肿瘤抑制因子1）在大多数转移性癌症中失活。DAL-1（在肺腺癌中差异表达的蛋白）是另一种肿瘤抑制因子，通过其FERM结构域结合到TSLC1 c端，4.1糖蛋白c样细胞质结构域。然而，这种相互作用的分子基础是未知的。在这里，我们描述了DAL-1 FERM结构域和部分TSLC1细胞质结构域之间的复合物的晶体结构。DAL-1通过在DAL-1 FERM结构域C-lobe结构中定义良好的疏水性口袋中的保守残基与TSLC1结合。从晶体结构上看，TSLC1细胞质域中Tyr（406）和Thr（408）与DAL-1形成了最重要的相互作用，表面等离子体共振研究也证实了这一点。我们的结果反驳了先前的外显子缺失实验，该实验表明糖蛋白C与4.1个FERM结构域的α叶相互作用。
Perturbed cell adhesion mechanisms are crucial for tumor invasion and metastasis. A cell adhesion protein, TSLC1 (tumor suppressor in lung cancer 1), is inactivated in a majority of metastatic cancers. DAL-1 (differentially expressed in adenocarcinoma of the lung protein), another tumor suppressor, binds through its FERM domain to the TSLC1 C-terminal, 4.1 glycophorin C-like, cytoplasmic domain. However, the molecular basis for this interaction is unknown. Here, we describe the crystal structure of a complex between the DAL-1 FERM domain and a portion of the TSLC1 cytoplasmic domain. DAL-1 binds to TSLC1 through conserved residues in a well defined hydrophobic pocket in the structural C-lobe of the DAL-1 FERM domain. From the crystal structure, it is apparent that Tyr(406) and Thr(408) in the TSLC1 cytoplasmic domain form the most important interactions with DAL-1, and this was also confirmed by surface plasmon resonance studies. Our results refute earlier exon deletion experiments that indicated that glycophorin C interacts with the alpha-lobe of 4.1 FERM domains.