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Human DECH-box RNA Helicase MDA5, DECH-domain

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PDB Code 3B6E Target Class ATPases Target MDA5 Alias Hlcd, IDDM19, IFIH1, MDA-5, MDA5, MGC133047 Disease Area/Function cancer Date Deposited Oct 29 2007 Authors T.KARLBERG, M.WELIN, ,C.H.ARROWSMITH, H.BERGLUND, R.D.BUSAM, R.COLLINS, L.G.DAHLGREN, A.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, I.JOHANSSON, A.KALLAS, T.KOTENYOVA, L.LEHTIO, M.MOCHE, M.E.NILSSON, P.NORDLUND, T.NYMAN, C.PERSSON, J.SAGEMARK, L.SVENSSON, A.G.THORSELL, L.TRESAUGUES, S.VAN DEN BERG, J.WEIGELT, L.HOLMBERG-SCHIAVONE

About this structure

The ATP-dependent DECH-box RNA helicase MDA5 (Melanoma differentiation-associated protein 5 also known as IFIH1 - Interferon-induced helicase C domain-containing protein 1) belongs to the DExD/H RNA-binding helicase family of proteins that are involved in all aspects of cellular RNA-metabolism such as transcription, splicing, RNA transport, translation and ribosome biogenesis. All proteins in this family bind and hydrolyze trinucleotides, mainly ATP, and are believed to function as RNA chaperones that bind RNA and assist in unwinding of RNA secondary structure or folding of RNA complexes. Members of this family normally consist of two domains: an N-terminal domain with the conserved DExD/H motif and a C-terminal helicase domain (Cordin et al. 2006).

MDA5 was discovered as being involved in the regulation of the growth and differentiation of melanoma cells (Kang et al. 2002). More recently MDA5 has been identified as a sensor of double-stranded viral RNA resulting in activation of anti-viral responses (Kato et al. 2006). The full-length protein contains two N-terminal CARD-domains (caspase recruitment domain) in addition to conserved domains 1 and 2 of DExD/H-box helicases. MDA5 triggers activation of a number transcription factors including IRF3, IRF7 and NF-B downstream in the signaling pathway (Unterholzner and Bowie 2007).

We have determined the three-dimensional structure of the conserved domain 1 (DECH-domain) of human MDA5 to a resolution of 1.6 Å. The structure was solved with SAD (single anomalous dispersion) method using selenomethione labeled protein. This is the first human structure of an RNA helicase with DExH-motif signature. The protein folds and resembles an α-β RecA-like domain. The N-terminal loop-helix seems important for packing in the crystal. No nucleotide is seen bound despite high concentrations of ADP and MgCl2 both in purification and during crystallization. Interestingly, the side chain from residue Arg337 is blocking access for binding of a nucleotide in the otherwise conserved binding pocket. The present structure will aid in the understanding of the human defense against viruses.

References

  1. Unterholzner L. and Bowie A.G. (2007) The interplay between viruses and innate immune signaling: Recent insights and therapeutic opportunities. Biochem. Pharmacol. Epub ahead of print
  2. Cordin O., Banroques J., Tanner N.K., and Linder P. (2006) The DEAD-box protein family of RNA helicases. Gene 367: 17-37.
  3. Kato H., Takeuchi O., Sato S., Yoneyama M., Yamamoto M., Matsui K., Uematsu S., Jung A., Kawai T., Ishii K.J., Yamaguchi O., Otsu K., Tsujimura T., Koh C-S., Reis e Sousa C., Matsuura Y., Fujita T. and Akira S. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441: 101-105.
  4. Kang D-C., Gopalkrishnan R.V., Wu Q., Jankowsky E., Pyle A.M. and Fisher P.B. (2002) mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. PNAS 99: 637-642.