Content deleted Content added
Added Structure section and edited Introduction |
No edit summary |
||
Line 9:
=== Protein ===
SMG6 is one of three human [[homologs]] for Est1p found in [[Saccharomyces cerevisiae]]. It contains a PIN domain, which is characteristic of proteins with [[ribonuclease]] activity.<ref>{{Cite journal|last=Glavan|first=Filip|last2=Behm-Ansmant|first2=Isabelle|last3=Izaurralde|first3=Elisa|last4=Conti|first4=Elena|date=2006-11-01|title=Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex|url=https://www.ncbi.nlm.nih.gov/pubmed/17053788|journal=The EMBO journal|volume=25|issue=21|pages=5117–5125|doi=10.1038/sj.emboj.7601377|issn=0261-4189|pmid=17053788}}</ref> The PIN domain forms an alpha/beta fold structure that similar to that found in 5' [[Nuclease|nucleases]].<ref>{{Cite journal|last=Takeshita|first=Daijiro|last2=Zenno|first2=Shuhei|last3=Lee|first3=Woo Cheol|last4=Saigo|first4=Kaoru|last5=Tanokura|first5=Masaru|date=2007-09-01|title=Crystal structure of the PIN domain of human telomerase-associated protein EST1A|url=https://www.ncbi.nlm.nih.gov/pubmed/17557331|journal=Proteins|volume=68|issue=4|pages=980–989|doi=10.1002/prot.21351|issn=1097-0134|pmid=17557331}}</ref> Within the PIN domain is a canonical triad of [[Amino acid|acidic residues]] that functions to cleave single-stranded RNA.<ref>{{Cite journal|last=Huntzinger|first=Eric|last2=Kashima|first2=Isao|last3=Fauser|first3=Maria|last4=Saulière|first4=Jérôme|last5=Izaurralde|first5=Elisa|date=2008-12-01|title=SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan|url=https://www.ncbi.nlm.nih.gov/pubmed/18974281|journal=RNA (New York, N.Y.)|volume=14|issue=12|pages=2609–2617|doi=10.1261/rna.1386208|issn=1469-9001|pmid=18974281}}</ref> SMG6 also shares a [[phosphoserine]]-binding domain resembling the one in [[14-3-3 protein|14–3–3 proteins]] with its other two homologs, [[SMG5]] and [[SMG7]]. This 14–3–3-like domain and a C-terminal helical hairpins domain with seven α-helices stacked perpendicular to the 14–3–3-like domain together form a monomeric tetratricopeptide region (TPR). Differences in the orientation and specific residues in the TPR between SMG6 and its homologs may account for why SMG6 does not form a [[Protein complexes|complex]] with SMG5 and SMG7 when recruited by [[UPF1]].<ref>{{Cite journal|last=Chakrabarti|first=Sutapa|last2=Bonneau|first2=Fabien|last3=Schüssler|first3=Steffen|last4=Eppinger|first4=Elfriede|last5=Conti|first5=Elena|date=2014-08-01|title=Phospho-dependent and phospho-independent interactions of the helicase UPF1 with the NMD factors SMG5-SMG7 and SMG6|url=https://www.ncbi.nlm.nih.gov/pubmed/25013172|journal=Nucleic Acids Research|volume=42|issue=14|pages=9447–9460|doi=10.1093/nar/gku578|issn=1362-4962|pmid=25013172}}</ref>
==Function==
SMG6 is broadly expressed in all human tissues. It has dual functions in [[telomere]] maintenance and [[RNA]] surveillance pathways. SMG6 binds single-stranded telomere DNA and cooperates with [[telomerase]] reverse transcriptase to lengthen telomeres.12699629<ref name="12699629">{{cite journal|last1=Snow|first1=BE|last2=Erdmann|first2=N|last3=Cruickshank|first3=J|last4=Goldman|first4=H|last5=Gill|first5=RM|last6=Robinson|first6=MO|last7=Harrington|first7=L|title=Functional conservation of the telomerase protein Est1p in humans.|journal=Current biology : CB|date=15 April 2003|volume=13|issue=8|pages=698-704|pmid=12699629}}</ref> Overexpression of SMG6 induces anaphase bridges due to chromosome-end fusions and, thus, affects telomere capping, which may directly induce an apoptotic response.<ref name="pmid10037601">{{cite journal|last1=Karlseder|first1=J|last2=Broccoli|first2=D|last3=Dai|first3=Y|last4=Hardy|first4=S|last5=de Lange|first5=T|title=p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2.|journal=Science (New York, N.Y.)|date=26 February 1999|volume=283|issue=5406|pages=1321-5|pmid=10037601}}</ref> <ref name="pmid12676087">{{cite journal|last1=Reichenbach|first1=P|last2=Höss|first2=M|last3=Azzalin|first3=CM|last4=Nabholz|first4=M|last5=Bucher|first5=P|last6=Lingner|first6=J|title=A human homolog of yeast Est1 associates with telomerase and uncaps chromosome ends when overexpressed.|journal=Current biology : CB|date=1 April 2003|volume=13|issue=7|pages=568-74|pmid=12676087}}</ref> SMG6 also functions as an [[endonuclease]] in the [[NMD]] pathway. The catalytic activity of SMG6 resides in its [[PIN]] domain, which is required for the degradation of [[premature translation termination codons]] (PTC)-containing mRNAs in human cells. <ref name="pmid18974281">{{cite journal|last1=Huntzinger|first1=E|last2=Kashima|first2=I|last3=Fauser|first3=M|last4=Saulière|first4=J|last5=Izaurralde|first5=E|title=SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan.|journal=RNA (New York, N.Y.)|date=December 2008|volume=14|issue=12|pages=2609-17|pmid=18974281}}</ref> SMG6 cleaves mRNA near the premature translocation-termination codons and requires [[UPF1]] and [[SMG1]] to reduce reporter mRNA levels.<ref name="pmid25053839">{{cite journal|last1=Nicholson|first1=P|last2=Josi|first2=C|last3=Kurosawa|first3=H|last4=Yamashita|first4=A|last5=Mühlemann|first5=O|title=A novel phosphorylation-independent interaction between SMG6 and UPF1 is essential for human NMD.|journal=Nucleic acids research|date=August 2014|volume=42|issue=14|pages=9217-35|pmid=25053839}}</ref>
== Clinical significance ==
| |||