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 DHX36gene.[1][2]
Structurally, DHX36 is a 1008 amino acid-long modular protein that has been crystallized in a complex with a DNA G-quadruplex.[3] 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.[4] 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.[5]
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.[6] They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrialsplicing, 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.[1]
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.
↑Abdelhaleem M, Maltais L, Wain H (June 2003). "The human DDX and DHX gene families of putative RNA helicases". Genomics. 81 (6): 618–22. doi:10.1016/S0888-7543(03)00049-1. PMID12782131.
↑Chen MC, Tippana R, Demeshkina NA, Murat P, Balasubramanian S, Myong S, Ferré-D'Amaré AR (June 2018). "Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36". Nature. 558 (7710): 465–469. doi:10.1038/s41586-018-0209-9. PMID29899445.
↑Chen WF, Rety S, Guo HL, Dai YX, Wu WQ, Liu NN, Auguin D, Liu QW, Hou XM, Dou SX, Xi XG (March 2018). "Molecular Mechanistic Insights into Drosophila DHX36-Mediated G-Quadruplex Unfolding: A Structure-Based Model". Structure. 26 (3): 403–415.e4. doi:10.1016/j.str.2018.01.008. PMID29429875.
↑Chen MC, Ferré-D'Amaré AR (15 August 2017). "Structural Basis of DEAH/RHA Helicase Activity". Crystals. 7 (8): 253. doi:10.3390/cryst7080253.
↑Vaughn JP, Creacy SD, Routh ED, Joyner-Butt C, Jenkins GS, Pauli S, Nagamine Y, Akman SA (November 2005). "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. doi:10.1074/jbc.C500348200. PMID16150737.
Nagase T, Kikuno R, Ishikawa K, Hirosawa M, Ohara O (April 2000). "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. doi:10.1093/dnares/7.2.143. PMID10819331.
Fu JJ, Li LY, Lu GX (September 2002). "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. PMID12198572.
Tran H, Schilling M, Wirbelauer C, Hess D, Nagamine Y (January 2004). "Facilitation of mRNA deadenylation and decay by the exosome-bound, DExH protein RHAU". Molecular Cell. 13 (1): 101–11. doi:10.1016/S1097-2765(03)00481-7. PMID14731398.
Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M, Peters EC (May 2004). "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. doi:10.1021/ac035352d. PMID15144186.
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 (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC1847948. PMID17353931.
