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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Structure of the human MTERF4–NSUN4 protein complex that regulates mitochondrial ribosome biogenesis
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Structure of the human MTERF4–NSUN4 protein complex that regulates mitochondrial ribosome biogenesis

机译：调节线粒体核糖体生物发生的人类MTERF4-NSUN4蛋白复合物的结构

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Proteins crucial for the respiratory chain are translated by the mitochondrial ribosome. Mitochondrial ribosome biogenesis is therefore critical for oxidative phosphorylation capacity and disturbances are known to cause human disease. This complex process is evolutionary conserved and involves several RNA processing and modification steps required for correct ribosomal RNA maturation. We recently showed that a member of the mitochondrial transcription termination factor (MTERF) family of proteins, MTERF4, recruits NSUN4, a 5-methylcytosine RNA methyltransferase, to the large ribosomal subunit in a process crucial for mitochondrial ribosome biogenesis. Here, we describe the 3D crystal structure of the human MTERF4–NSUN4 complex determined to 2.9 Å resolution. MTERF4 is composed of structurally repeated MTERF–motifs that form a nucleic acid binding domain. NSUN4 lacks an N- or C-terminal extension that is commonly used for RNA recognition by related RNA methyltransferases. Instead, NSUN4 binds to the C-terminus of MTERF4. A positively charged surface forms an RNA binding path from the concave to the convex side of MTERF4 and further along NSUN4 all of the way into the active site. This finding suggests that both subunits of the protein complex likely contribute to RNA recognition. The interface between MTERF4 and NSUN4 contains evolutionarily conserved polar and hydrophobic amino acids, and mutations that change these residues completely disrupt complex formation. This study provides a molecular explanation for MTERF4-dependent recruitment of NSUN4 to ribosomal RNA and suggests a unique mechanism by which other members of the large MTERF-family of proteins can regulate ribosomal biogenesis.
机译：对于呼吸链至关重要的蛋白质由线粒体核糖体翻译。因此，线粒体核糖体的生物发生对于氧化磷酸化能力至关重要，已知干扰会导致人类疾病。这个复杂的过程是进化保守的，涉及正确的核糖体RNA成熟所需的几个RNA处理和修饰步骤。我们最近显示，线粒体转录终止因子（MTERF）蛋白家族成员MTERF4在对线粒体核糖体生物发生至关重要的过程中将NSUN4（一种5-甲基胞嘧啶RNA甲基转移酶）募集到大核糖体亚基。在这里，我们描述了以2.9Å分辨率确定的人类MTERF4-NSUN4复合物的3D晶体结构。 MTERF4由结构重复的MTERF-基序组成，形成核酸结合域。 NSUN4缺少通常用于相关RNA甲基转移酶的RNA识别的N端或C端延伸。相反，NSUN4绑定到MTERF4的C末端。带正电的表面形成从MTERF4的凹面到凸面，再沿着NSUN4一直进入活性位点的RNA结合路径。这一发现表明，蛋白质复合物的两个亚基都可能有助于RNA的识别。 MTERF4和NSUN4之间的界面包含进化上保守的极性和疏水氨基酸，改变这些残基的突变完全破坏了复合物的形成。这项研究为依赖MTERF4的NSUN4募集到核糖体RNA提供了分子解释，并提出了独特的机制，大MTERF蛋白家族的其他成员可以通过该机制调节核糖体的生物发生。

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