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Article
Subject Categories: RNA | Structural Biology
The EMBO Journal (2006) 25, 5117–5125, doi:10.1038/sj.emboj.7601377
Published online 19 October 2006
Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex
Filip Glavan1, Isabelle Behm-Ansmant2, Elisa Izaurralde2 and Elena Conti1, 3
1 European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
2 Max-Planck-Institute for Developmental Biology, Tübingen, Germany
3 Max-Planck-Institute of Biochemistry, Martinsried, Germany

To whom correspondence should be addressed
Elena Conti, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, Heidelberg 69117, Germany. Tel.: +49 6221 387 536; Fax: +49 6221 387 306; E-mail: conti@embl-heidelberg.de or conti@embl.de

Received 26 May 2006; Accepted 7 September 2006; Published online 19 October 2006.
Abstract
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 ribonucleases 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.
Keywords: decay, EST1A, NMD, P-bodies, RNA degradation
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