5vhe
From Proteopedia
DHX36 in complex with the c-Myc G-quadruplex
Structural highlights
FunctionDHX36_BOVIN Multifunctional ATP-dependent helicase that unwinds G-quadruplex (G4) structures (PubMed:29899445). Plays a role in many biological processes such as genomic integrity, gene expression regulations and as a sensor to initiate antiviral responses (By similarity). G4 structures correspond to helical structures containing guanine tetrads (PubMed:29899445). Binds with high affinity to and unwinds G4 structures that are formed in nucleic acids (G4-ADN and G4-RNA) (PubMed:29899445) (By similarity). Plays a role in genomic integrity. Converts the G4-RNA structure present in telomerase RNA template component (TREC) into a double-stranded RNA to promote P1 helix formation that acts as a template boundary ensuring accurate reverse transcription (By similarity). Plays a role in transcriptional regulation. Resolves G4-DNA structures in promoters of genes, such as YY1, KIT/c-kit and ALPL and positively regulates their expression (By similarity). Plays a role in post-transcriptional regulation. Unwinds a G4-RNA structure located in the 3'-UTR polyadenylation site of the pre-mRNA TP53 and stimulates TP53 pre-mRNA 3'-end processing in response to ultraviolet (UV)-induced DNA damage (By similarity). Binds to the precursor-microRNA-134 (pre-miR-134) terminal loop and regulates its transport into the synapto-dendritic compartment (By similarity). Involved in the pre-miR-134-dependent inhibition of target gene expression and the control of dendritic spine size (By similarity). Plays a role in the regulation of cytoplasmic mRNA translation and mRNA stability (By similarity). Binds to both G4-RNA structures and alternative non-quadruplex-forming sequence within the 3'-UTR of the PITX1 mRNA regulating negatively PITX1 protein expression (By similarity). Binds to both G4-RNA structure in the 5'-UTR and AU-rich elements (AREs) localized in the 3'-UTR of NKX2-5 mRNA to either stimulate protein translation or induce mRNA decay in an ELAVL1-dependent manner, respectively (By similarity). Binds also to ARE sequences present in several mRNAs mediating exosome-mediated 3'-5' mRNA degradation (By similarity). Involved in cytoplasmic urokinase-type plasminogen activator (uPA) mRNA decay (By similarity). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines via the adapter molecule TICAM1 (By similarity). Required for the early embryonic development and hematopoiesis. Involved in the regulation of cardioblast differentiation and proliferation during heart development. Involved in spermatogonia differentiation. May play a role in ossification (By similarity).[UniProtKB:D4A2Z8][UniProtKB:Q8VHK9][UniProtKB:Q9H2U1][1] Publication Abstract from PubMedGuanine-rich nucleic acid sequences challenge the replication, transcription, and translation machinery by spontaneously folding into G-quadruplexes, the unfolding of which requires forces greater than most polymerases can exert(1,2). Eukaryotic cells contain numerous helicases that can unfold G-quadruplexes (3) . The molecular basis of the recognition and unfolding of G-quadruplexes by helicases remains poorly understood. DHX36 (also known as RHAU and G4R1), a member of the DEAH/RHA family of helicases, binds both DNA and RNA G-quadruplexes with extremely high affinity(4-6), is consistently found bound to G-quadruplexes in cells(7,8), and is a major source of G-quadruplex unfolding activity in HeLa cell lysates (6) . DHX36 is a multi-functional helicase that has been implicated in G-quadruplex-mediated transcriptional and post-transcriptional regulation, and is essential for heart development, haematopoiesis, and embryogenesis in mice(9-12). Here we report the co-crystal structure of bovine DHX36 bound to a DNA with a G-quadruplex and a 3' single-stranded DNA segment. We show that the N-terminal DHX36-specific motif folds into a DNA-binding-induced alpha-helix that, together with the OB-fold-like subdomain, selectively binds parallel G-quadruplexes. Comparison with unliganded and ATP-analogue-bound DHX36 structures, together with single-molecule fluorescence resonance energy transfer (FRET) analysis, suggests that G-quadruplex binding alone induces rearrangements of the helicase core; by pulling on the single-stranded DNA tail, these rearrangements drive G-quadruplex unfolding one residue at a time. Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36.,Chen MC, Tippana R, Demeshkina NA, Murat P, Balasubramanian S, Myong S, Ferre-D'Amare AR Nature. 2018 Jun 13. pii: 10.1038/s41586-018-0209-9. doi:, 10.1038/s41586-018-0209-9. PMID:29899445[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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