Crystal structure of the Lin28-interacting module of human terminal uridylyltransferase that regulates let-7 expression
Crystal structure of the Lin28-interacting module of human terminal uridylyltransferase that regulates let-7 expression
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DOI：
10.1038/s41467-019-09966-5
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发表时间：
2019-04
影响因子：
16.6
通讯作者：
S. Yamashita;Takashi Nagaike;K. Tomita
中科院分区：
文献类型：
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作者：
S. Yamashita;Takashi Nagaike;K. Tomita
通过末端尿苷酰转移酶4/7（TUT 4/7）对前体let-7（pre-let-7）的Lin 28依赖性寡尿苷酰化通过阻断Dicer加工来抑制let-7表达，并调节细胞分化和增殖。Lin 28：pre-let-7复合物与TUT 4/7的N-末端Lin 28相互作用模块（LIM）之间的相互作用是TUT 4/7的C-末端催化模块（CM）进行pre-let-7寡尿苷酰化所必需的。在这里，我们报告了对人类TUT 4 LIM的晶体学和生化分析。LIM由N-末端Cys 2 His 2型锌指（ZF）和非催化核苷酸转移酶结构域（nc-NTD）组成。LIM的ZF具有独特的结构域，其结构与双链RNA结合锌指的结构同源。ZF和pre-let-7之间的相互作用稳定了Lin 28：pre-let-7：TUT 4三元复合物，并增强了CM的寡聚尿苷酰化反应。因此，LIM中的ZF和CM中的锌节与寡聚尿苷酰化尾部相互作用，共同促进Lin 28依赖性pre-let-7寡聚尿苷酰化。
Lin28-dependent oligo-uridylylation of precursor let-7 (pre-let-7) by terminal uridylyltransferase 4/7 (TUT4/7) represses let-7 expression by blocking Dicer processing, and regulates cell differentiation and proliferation. The interaction between the Lin28:pre-let-7 complex and the N-terminal Lin28-interacting module (LIM) of TUT4/7 is required for pre-let-7 oligo-uridylylation by the C-terminal catalytic module (CM) of TUT4/7. Here, we report crystallographic and biochemical analyses of the LIM of human TUT4. The LIM consists of the N-terminal Cys2His2-type zinc finger (ZF) and the non-catalytic nucleotidyltransferase domain (nc-NTD). The ZF of LIM adopts a distinct structural domain, and its structure is homologous to those of double-stranded RNA binding zinc fingers. The interaction between the ZF and pre-let-7 stabilizes the Lin28:pre-let-7:TUT4 ternary complex, and enhances the oligo-uridylylation reaction by the CM. Thus, the ZF in LIM and the zinc-knuckle in the CM, which interacts with the oligo-uridylylated tail, together facilitate Lin28-dependent pre-let-7 oligo-uridylylation.