5b16

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X-ray structure of DROSHA in complex with the C-terminal tail of DGCR8.X-ray structure of DROSHA in complex with the C-terminal tail of DGCR8.

Structural highlights

5b16 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:
Gene:DROSHA, RN3, RNASE3L, RNASEN (HUMAN), DGCR8, C22orf12, DGCRK6, LP4941 (HUMAN)
Activity:Ribonuclease III, with EC number 3.1.26.3
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[RNC_HUMAN] Ribonuclease III double-stranded (ds) RNA-specific endoribonuclease that is involved in the initial step of microRNA (miRNA) biogenesis. Component of the microprocessor complex that is required to process primary miRNA transcripts (pri-miRNAs) to release precursor miRNA (pre-miRNA) in the nucleus. Within the microprocessor complex, DROSHA cleaves the 3' and 5' strands of a stem-loop in pri-miRNAs (processing center 11 bp from the dsRNA-ssRNA junction) to release hairpin-shaped pre-miRNAs that are subsequently cut by the cytoplasmic DICER to generate mature miRNAs. Involved also in pre-rRNA processing. Cleaves double-strand RNA and does not cleave single-strand RNA. Involved in the formation of GW bodies.[1] [2] [3] [4] [5] [6] [7] [8] [9] [DGCR8_HUMAN] Component of the microprocessor complex that acts as a RNA- and heme-binding protein that is involved in the initial step of microRNA (miRNA) biogenesis. Component of the microprocessor complex that is required to process primary miRNA transcripts (pri-miRNAs) to release precursor miRNA (pre-miRNA) in the nucleus. Within the microprocessor complex, DGCR8 function as a molecular anchor necessary for the recognition of pri-miRNA at dsRNA-ssRNA junction and directs DROSHA to cleave 11 bp away form the junction to release hairpin-shaped pre-miRNAs that are subsequently cut by the cytoplasmic DICER to generate mature miRNAs. The heme-bound DGCR8 dimer binds pri-miRNAs as a cooperative trimer (of dimers) and is active in triggering pri-miRNA cleavage, whereas the heme-free DGCR8 monomer binds pri-miRNAs as a dimer and is much less active. Both double-stranded and single-stranded regions of a pri-miRNA are required for its binding. Involved in the silencing of embryonic stem cells self-renewal.[10] [11] [12] [13] [14] [15] [16]

Publication Abstract from PubMed

MicroRNA maturation is initiated by RNase III DROSHA that cleaves the stem loop of primary microRNA. DROSHA functions together with its cofactor DGCR8 in a heterotrimeric complex known as Microprocessor. Here, we report the X-ray structure of DROSHA in complex with the C-terminal helix of DGCR8. We find that DROSHA contains two DGCR8-binding sites, one on each RNase III domain (RIIID), which mediate the assembly of Microprocessor. The overall structure of DROSHA is surprisingly similar to that of Dicer despite no sequence homology apart from the C-terminal part, suggesting that DROSHA may have evolved from a Dicer homolog. DROSHA exhibits unique features, including non-canonical zinc-finger motifs, a long insertion in the first RIIID, and the kinked link between Connector helix and RIIID, which explains the 11-bp-measuring "ruler" activity of DROSHA. Our study implicates the evolutionary origin of DROSHA and elucidates the molecular basis of Microprocessor assembly and primary microRNA processing. VIDEO ABSTRACT.

Structure of Human DROSHA.,Kwon SC, Nguyen TA, Choi YG, Jo MH, Hohng S, Kim VN, Woo JS Cell. 2016 Jan 14;164(1-2):81-90. doi: 10.1016/j.cell.2015.12.019. Epub 2015 Dec , 31. PMID:26748718[17]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Wu H, Xu H, Miraglia LJ, Crooke ST. Human RNase III is a 160-kDa protein involved in preribosomal RNA processing. J Biol Chem. 2000 Nov 24;275(47):36957-65. PMID:10948199 doi:http://dx.doi.org/10.1074/jbc.M005494200
  2. ↑ Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S, Kim VN. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003 Sep 25;425(6956):415-9. PMID:14508493 doi:http://dx.doi.org/10.1038/nature01957
  3. ↑ Landthaler M, Yalcin A, Tuschl T. The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis. Curr Biol. 2004 Dec 14;14(23):2162-7. PMID:15589161 doi:10.1016/j.cub.2004.11.001
  4. ↑ Han J, Lee Y, Yeom KH, Kim YK, Jin H, Kim VN. The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev. 2004 Dec 15;18(24):3016-27. Epub 2004 Dec 1. PMID:15574589 doi:10.1101/gad.1262504
  5. ↑ Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R. The Microprocessor complex mediates the genesis of microRNAs. Nature. 2004 Nov 11;432(7014):235-40. Epub 2004 Nov 7. PMID:15531877 doi:10.1038/nature03120
  6. ↑ Zeng Y, Yi R, Cullen BR. Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha. EMBO J. 2005 Jan 12;24(1):138-48. Epub 2004 Nov 25. PMID:15565168 doi:http://dx.doi.org/10.1038/sj.emboj.7600491
  7. ↑ Han J, Lee Y, Yeom KH, Nam JW, Heo I, Rhee JK, Sohn SY, Cho Y, Zhang BT, Kim VN. Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell. 2006 Jun 2;125(5):887-901. PMID:16751099 doi:10.1016/j.cell.2006.03.043
  8. ↑ Pauley KM, Eystathioy T, Jakymiw A, Hamel JC, Fritzler MJ, Chan EK. Formation of GW bodies is a consequence of microRNA genesis. EMBO Rep. 2006 Sep;7(9):904-10. Epub 2006 Aug 11. PMID:16906129 doi:7400783
  9. ↑ Faller M, Matsunaga M, Yin S, Loo JA, Guo F. Heme is involved in microRNA processing. Nat Struct Mol Biol. 2007 Jan;14(1):23-9. Epub 2006 Dec 10. PMID:17159994 doi:10.1038/nsmb1182
  10. ↑ Landthaler M, Yalcin A, Tuschl T. The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis. Curr Biol. 2004 Dec 14;14(23):2162-7. PMID:15589161 doi:10.1016/j.cub.2004.11.001
  11. ↑ Han J, Lee Y, Yeom KH, Kim YK, Jin H, Kim VN. The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev. 2004 Dec 15;18(24):3016-27. Epub 2004 Dec 1. PMID:15574589 doi:10.1101/gad.1262504
  12. ↑ Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R. The Microprocessor complex mediates the genesis of microRNAs. Nature. 2004 Nov 11;432(7014):235-40. Epub 2004 Nov 7. PMID:15531877 doi:10.1038/nature03120
  13. ↑ Han J, Lee Y, Yeom KH, Nam JW, Heo I, Rhee JK, Sohn SY, Cho Y, Zhang BT, Kim VN. Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell. 2006 Jun 2;125(5):887-901. PMID:16751099 doi:10.1016/j.cell.2006.03.043
  14. ↑ Pauley KM, Eystathioy T, Jakymiw A, Hamel JC, Fritzler MJ, Chan EK. Formation of GW bodies is a consequence of microRNA genesis. EMBO Rep. 2006 Sep;7(9):904-10. Epub 2006 Aug 11. PMID:16906129 doi:7400783
  15. ↑ Yeom KH, Lee Y, Han J, Suh MR, Kim VN. Characterization of DGCR8/Pasha, the essential cofactor for Drosha in primary miRNA processing. Nucleic Acids Res. 2006;34(16):4622-9. Epub 2006 Sep 8. PMID:16963499 doi:10.1093/nar/gkl458
  16. ↑ Faller M, Matsunaga M, Yin S, Loo JA, Guo F. Heme is involved in microRNA processing. Nat Struct Mol Biol. 2007 Jan;14(1):23-9. Epub 2006 Dec 10. PMID:17159994 doi:10.1038/nsmb1182
  17. ↑ Kwon SC, Nguyen TA, Choi YG, Jo MH, Hohng S, Kim VN, Woo JS. Structure of Human DROSHA. Cell. 2016 Jan 14;164(1-2):81-90. doi: 10.1016/j.cell.2015.12.019. Epub 2015 Dec , 31. PMID:26748718 doi:http://dx.doi.org/10.1016/j.cell.2015.12.019

5b16, resolution 3.20Å

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