DHX36 explained

Probable ATP-dependent RNA helicase DHX36 also known as DEAH box protein 36 (DHX36) or MLE-like protein 1 (MLEL1) or G4 resolvase 1 (G4R1) or RNA helicase associated with AU-rich elements (RHAU) is an enzyme that in humans is encoded by the DHX36 gene.^[1]

Structure

Structurally, DHX36 is a 1008 amino acid-long modular protein that has been crystallized in a complex with a DNA G-quadruplex.^[2] It consists of a ~440-amino acid helicase core comprising all signature motifs of the DEAH/RHA family of helicases with N- and C-terminal flanking regions of ~180 and ~380 amino acids, respectively. Part of the N-terminal flanking region forms an alpha-helix called the DHX36-specific motif, which recognizes the 5'-most G-quadruplex quartet. The OB-fold domain binds to the 3'-most G-tract sugar-phosphate backbone.^[3] Like all the DEAH/RHA helicases, the helicase associated domain is located adjacent to the helicase core region and occupies 75% of the C-terminal region.^[4]

Function

DEAH/RHA proteins are RNA and DNA helicases typically characterized by low processivity translocation on substrates and the capability to bind/unwind non-canonical nucleic acid secondary structures.^[5] They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this DEAH/RHA protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division.^[6]

DHX36 exhibits a unique ATP-dependent guanine-quadruplex (G4) resolvase activity and specificity for its substrate in vitro.^{[7] [8]} DHX36 displays repetitive unwinding activity as a function of the thermal stability of the G-quadruplex substrate, characteristic of a number of other G-quadruplex resolvases such as the BLM/WRN helicases.^{[9] [10]} DHX36 binds G4-nucleic acid with sub-nanomolar affinity and unwinds G4 structures much more efficiently than double-stranded nucleic acid. Consistent with these biochemical observations, DHX36 was also identified as the major source of tetramolecular RNA-resolving activity in HeLa cell lysates.

Previous work showed that DHX36 associates with mRNAs and re-localises to stress granules (SGs) upon translational arrest induced by various environmental stresses.^{[11] [12]} A region of the first 105 amino acid was shown to be critical for RNA binding and re-localisation to SGs.

Further reading

• Nagase T, Kikuno R, Ishikawa K, Hirosawa M, Ohara O . Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 7 . 2 . 143–50 . April 2000 . 10819331 . 10.1093/dnares/7.2.143 . free .
• Fu JJ, Li LY, Lu GX . Molecular cloning and characterization of human DDX36 and mouse Ddx36 genes, new members of the DEAD/H box superfamily . Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao Acta Biochimica et Biophysica Sinica . 34 . 5 . 655–61 . September 2002 . 12198572 .
• Tran H, Schilling M, Wirbelauer C, Hess D, Nagamine Y . Facilitation of mRNA deadenylation and decay by the exosome-bound, DExH protein RHAU . Molecular Cell . 13 . 1 . 101–11 . January 2004 . 14731398 . 10.1016/S1097-2765(03)00481-7 . free .
• Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M, Peters EC . Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry . Analytical Chemistry . 76 . 10 . 2763–72 . May 2004 . 15144186 . 10.1021/ac035352d .
• Brown V, Brown RA, Ozinsky A, Hesselberth JR, Fields S . Binding specificity of Toll-like receptor cytoplasmic domains . European Journal of Immunology . 36 . 3 . 742–53 . March 2006 . 16482509 . 2762736 . 10.1002/eji.200535158 .
• Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D . Large-scale mapping of human protein-protein interactions by mass spectrometry . Molecular Systems Biology . 3 . 1 . 89 . 2007 . 17353931 . 1847948 . 10.1038/msb4100134 .

External links

• Group Yoshikuni Nagamine homepage
• Group Steven Akman homepage

Notes and References

1. Abdelhaleem M, Maltais L, Wain H . The human DDX and DHX gene families of putative RNA helicases . Genomics . 81 . 6 . 618–22 . June 2003 . 12782131 . 10.1016/S0888-7543(03)00049-1 .
2. Chen MC, Tippana R, Demeshkina NA, Murat P, Balasubramanian S, Myong S, Ferré-D'Amaré AR . Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36 . Nature . 558 . 7710 . 465–469 . June 2018 . 29899445 . 6261253 . 10.1038/s41586-018-0209-9 . 2018Natur.558..465C .
3. Heddi B, Cheong VV, Martadinata H, Phan AT . Insights into G-quadruplex specific recognition by the DEAH-box helicase RHAU: Solution structure of a peptide-quadruplex complex . Proc. Natl. Acad. Sci. U.S.A. . 112 . 31 . 9608–13 . August 2015 . 26195789 . 4534227 . 10.1073/pnas.1422605112 . 2015PNAS..112.9608H . free .
4. Chen WF, Rety S, Guo HL, Dai YX, Wu WQ, Liu NN, Auguin D, Liu QW, Hou XM, Dou SX, Xi XG . Molecular Mechanistic Insights into Drosophila DHX36-Mediated G-Quadruplex Unfolding: A Structure-Based Model . Structure . 26 . 3 . 403–415.e4 . March 2018 . 29429875 . 10.1016/j.str.2018.01.008 . free .
5. Chen MC, Ferré-D'Amaré AR . Structural Basis of DEAH/RHA Helicase Activity . Crystals . 15 August 2017 . 7 . 8 . 253 . 10.3390/cryst7080253 . free .
6. Web site: Entrez Gene: DHX36 DEAH (Asp-Glu-Ala-His) box polypeptide 36.
7. Vaughn JP, Creacy SD, Routh ED, Joyner-Butt C, Jenkins GS, Pauli S, Nagamine Y, Akman SA . The DEXH protein product of the DHX36 gene is the major source of tetramolecular quadruplex G4-DNA resolving activity in HeLa cell lysates . The Journal of Biological Chemistry . 280 . 46 . 38117–20 . November 2005 . 16150737 . 10.1074/jbc.C500348200 . free .
8. Creacy SD, Routh ED, Iwamoto F, Nagamine Y, Akman SA, Vaughn JP . G4 resolvase 1 binds both DNA and RNA tetramolecular quadruplex with high affinity and is the major source of tetramolecular quadruplex G4-DNA and G4-RNA resolving activity in HeLa cell lysates . The Journal of Biological Chemistry . 283 . 50 . 34626–34 . December 2008 . 18842585 . 2596407 . 10.1074/jbc.M806277200 . free .
9. Chen MC, Murat P, Abecassis K, Ferré-D'Amaré AR, Balasubramanian S . Insights into the mechanism of a G-quadruplex-unwinding DEAH-box helicase . Nucleic Acids Res. . 43 . 4 . 2223–31 . February 2015 . 25653156 . 4344499 . 10.1093/nar/gkv051 .
10. Tippana R, Hwang H, Opresko PL, Bohr VA, Myong S . Single-molecule imaging reveals a common mechanism shared by G-quadruplex-resolving helicases . Proc. Natl. Acad. Sci. U.S.A. . 113 . 30 . 8448–53 . July 2016 . 27407146 . 4968719 . 10.1073/pnas.1603724113 . 2016PNAS..113.8448T . free .
11. Chalupníková K, Lattmann S, Selak N, Iwamoto F, Fujiki Y, Nagamine Y . Recruitment of the RNA helicase RHAU to stress granules via a unique RNA-binding domain . The Journal of Biological Chemistry . 283 . 50 . 35186–98 . December 2008 . 18854321 . 3259895 . 10.1074/jbc.M804857200 . free .
12. Web site: Kateřina . Chalupníková . 2008 . Characterizing functional domains of the RNA helicase RHAU involved in subcellular localization and RNA interaction.