Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex
Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex
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DOI：
10.1038/sj.emboj.7601377
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发表时间：
2006-11-01
期刊：
影响因子：
11.4
通讯作者：
Conti, Elena
中科院分区：
文献类型：
--
作者：
Glavan, Filip;Behm-Ansmant, Isabelle;Conti, Elena
SMG6和SMG5是无义介导的信使核糖核酸降解的关键因子，无义信使信使核糖核酸降解的保守途径是提前翻译终止密码子。SMG5和SMG6都被预测含有一个C-末端PIN(PILT N-末端)结构域，存在于具有核糖核酸酶活性的蛋白质中。我们已经确定了人SMG5和SMG6 PIN结构域的结构。尽管它们与RNaseH家族的核糖核酸酶有相似的总体折叠，但它们在假定的活性位点上存在局部差异。SMG6具有典型的三个酸性残基，这些残基在RNaseH中对核酸酶活性至关重要，而SMG5缺乏关键的催化残基。结构性差异反映在职能层面。只有SMG6的PIN结构域在体外对单链RNA具有降解活性。这种催化活性的差异在果蝇中是保守的，具有非活性PIN结构域的SMG6以显性-负向方式抑制NMD。我们的发现表明，NMD机制具有内在的核酸酶活性，这可能有助于提前终止翻译的mRNAs的快速衰退。
SMG6 and SMG5 are essential factors in nonsense-mediated mRNA decay, a conserved pathway that degrades mRNAs with premature translation termination codons. Both SMG5 and SMG6 have been predicted to contain a C-terminal PIN (PilT N-terminus) domain, present in proteins with ribonuclease activity. We have determined the structures of human SMG5 and SMG6 PIN domains. Although they share a similar overall fold related to ribo-nucleases of the RNase H family, they have local differences at the putative active site. SMG6 has the canonical triad of acidic residues that are crucial in RNase H for nuclease activity, while SMG5 lacks key catalytic residues. The structural differences are reflected at the functional level. Only the PIN domain of SMG6 has degradation activity on single-stranded RNA in vitro. This difference in catalytic activity is conserved in Drosophila, where an SMG6 with an inactive PIN domain inhibits NMD in a dominant-negative manner. Our findings suggest that the NMD machinery has intrinsic nuclease activity that is likely to contribute to the rapid decay of mRNAs that terminate translation prematurely.