Poy F, Lepourcelet M, Shivdasani R A, Eck M J
Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
Nat Struct Biol. 2001 Dec;8(12):1053-7. doi: 10.1038/nsb720.
The multifunctional protein beta-catenin is important for cell adhesion, because it binds cadherins, and the Wnt signal transduction pathway, where it interacts with the Adenomatous polyposis coli (APC) protein and TCF/Lef family transcription factors. Mutations in APC or in beta-catenin are estimated to trigger formation of over 90% of all colon cancers. In colonic epithelia, these mutations produce elevated levels of Tcf4-beta-catenin, which stimulates a transcriptional response that initiates polyp formation and eventually malignant growth. Thus, disruption of the Tcf4-beta-catenin interaction may be an attractive goal for therapeutic intervention. Here we describe the crystal structure of a human Tcf4-beta-catenin complex and compare it with recent structures of beta-catenin in complex with Xenopus Tcf3 (XTcf3) and mammalian E-cadherin. The structure reveals anticipated similarities with the closely related XTcf3 complex but unexpectedly lacks one component observed in the XTcf3 structure.
多功能蛋白β-连环蛋白对细胞黏附很重要，因为它能结合钙黏蛋白，并且在Wnt信号转导途径中发挥作用，在该途径中它与腺瘤性息肉病大肠杆菌（APC）蛋白以及TCF/Lef家族转录因子相互作用。据估计，APC或β-连环蛋白中的突变会引发超过90%的结肠癌形成。在结肠上皮细胞中，这些突变会导致Tcf4-β-连环蛋白水平升高，从而刺激一种转录反应，引发息肉形成并最终发展为恶性生长。因此，破坏Tcf4-β-连环蛋白的相互作用可能是一个有吸引力的治疗干预目标。在此，我们描述了人Tcf4-β-连环蛋白复合物的晶体结构，并将其与β-连环蛋白与非洲爪蟾Tcf3（XTcf3）和哺乳动物E-钙黏蛋白形成的复合物的最新结构进行比较。该结构显示出与密切相关的XTcf3复合物预期的相似性，但出乎意料的是缺少XTcf3结构中观察到的一个组分。
