DENR-MCT-1 复合物的晶体结构揭示了锌结合位点对于异二聚体形成的必要性。
Crystal structure of the DENR-MCT-1 complex revealed zinc-binding site essential for heterodimer formation.
机构信息
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114;
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia.
出版信息
Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):528-533. doi: 10.1073/pnas.1809688116. Epub 2018 Dec 24.
The density-regulated protein (DENR) and the malignant T cell-amplified sequence 1 (MCT-1/MCTS1) oncoprotein support noncanonical translation initiation, promote translation reinitiation on a specific set of mRNAs with short upstream reading frames, and regulate ribosome recycling. DENR and MCT-1 form a heterodimer, which binds to the ribosome. We determined the crystal structure of the heterodimer formed by human MCT-1 and the N-terminal domain of DENR at 2.0-Å resolution. The structure of the heterodimer reveals atomic details of the mechanism of DENR and MCT-1 interaction. Four conserved cysteine residues of DENR (C34, C37, C44, C53) form a classical tetrahedral zinc ion-binding site, which preserves the structure of the DENR's MCT-1-binding interface that is essential for the dimerization. Substitution of all four cysteines by alanine abolished a heterodimer formation. Our findings elucidate further the mechanism of regulation of DENR-MCT-1 activities in unconventional translation initiation, reinitiation, and recycling.
密度调节蛋白（DENR）和恶性 T 细胞扩增序列 1（MCT-1/MCTS1）癌蛋白支持非典型翻译起始，促进具有短上游阅读框的特定一组 mRNA 的翻译重新起始，并调节核糖体回收。DENR 和 MCT-1 形成异二聚体，与核糖体结合。我们以 2.0-Å 的分辨率确定了人 MCT-1 和 DENR N 端结构域形成的异二聚体的晶体结构。异二聚体的结构揭示了 DENR 和 MCT-1 相互作用机制的原子细节。DENR 的四个保守半胱氨酸残基（C34、C37、C44、C53）形成经典的四面体型锌离子结合位点，保留了 DENR 的 MCT-1 结合界面的结构，这对于二聚化是必需的。用丙氨酸取代所有四个半胱氨酸完全消除了异二聚体的形成。我们的发现进一步阐明了 DENR-MCT-1 在非典型翻译起始、重新起始和回收中的活性调节机制。
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