Proteopedia

3l11

Crystal Structure of the Ring Domain of RNF168Crystal Structure of the Ring Domain of RNF168

Structural highlights

3l11 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.12Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

RN168_HUMAN Defects in RNF168 are the cause of Riddle syndrome (RIDDLES) [MIM:611943. Riddle syndrome is characterized by increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature. Defects are probably due to impaired localization of TP53BP1 and BRCA1 at DNA lesions.[1]

Function

RN168_HUMAN E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the RNF8-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).[2] [3] [4] [5] [6] [7] [8] [9]

Evolutionary Conservation

 

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The repair of DNA double strand breaks by homologous recombination relies on the unique topology of the chains formed by Lys-63 ubiquitylation of chromatin to recruit repair factors such as breast cancer 1 (BRCA1) to sites of DNA damage. The human RING finger (RNF) E3 ubiquitin ligases, RNF8 and RNF168, with the E2 ubiquitin-conjugating complex Ubc13/Mms2, perform the majority of Lys-63 ubiquitylation in homologous recombination. Here, we show that RNF8 dimerizes and binds to Ubc13/Mms2, thereby stimulating formation of Lys-63 ubiquitin chains, whereas the related RNF168 RING domain is a monomer and does not catalyze Lys-63 polyubiquitylation. The crystal structure of the RNF8/Ubc13/Mms2 ternary complex reveals the structural basis for the interaction between Ubc13 and the RNF8 RING and that an extended RNF8 coiled-coil is responsible for its dimerization. Mutations that disrupt the RNF8/Ubc13 binding surfaces, or that truncate the RNF8 coiled-coil, reduce RNF8-catalyzed ubiquitylation. These findings support the hypothesis that RNF8 is responsible for the initiation of Lys-63-linked ubiquitylation in the DNA damage response, which is subsequently amplified by RNF168.

Molecular Insights into the Function of RING Finger (RNF)-containing Proteins hRNF8 and hRNF168 in Ubc13/Mms2-dependent Ubiquitylation.,Campbell SJ, Edwards RA, Leung CC, Neculai D, Hodge CD, Dhe-Paganon S, Glover JN J Biol Chem. 2012 Jul 6;287(28):23900-10. Epub 2012 May 15. PMID:22589545[10]

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

See Also

References

  1. ↑ Stewart GS, Panier S, Townsend K, Al-Hakim AK, Kolas NK, Miller ES, Nakada S, Ylanko J, Olivarius S, Mendez M, Oldreive C, Wildenhain J, Tagliaferro A, Pelletier L, Taubenheim N, Durandy A, Byrd PJ, Stankovic T, Taylor AM, Durocher D. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell. 2009 Feb 6;136(3):420-34. doi: 10.1016/j.cell.2008.12.042. PMID:19203578 doi:10.1016/j.cell.2008.12.042
  2. ↑ Stewart GS, Panier S, Townsend K, Al-Hakim AK, Kolas NK, Miller ES, Nakada S, Ylanko J, Olivarius S, Mendez M, Oldreive C, Wildenhain J, Tagliaferro A, Pelletier L, Taubenheim N, Durandy A, Byrd PJ, Stankovic T, Taylor AM, Durocher D. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell. 2009 Feb 6;136(3):420-34. doi: 10.1016/j.cell.2008.12.042. PMID:19203578 doi:10.1016/j.cell.2008.12.042
  3. ↑ Doil C, Mailand N, Bekker-Jensen S, Menard P, Larsen DH, Pepperkok R, Ellenberg J, Panier S, Durocher D, Bartek J, Lukas J, Lukas C. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell. 2009 Feb 6;136(3):435-46. doi: 10.1016/j.cell.2008.12.041. PMID:19203579 doi:10.1016/j.cell.2008.12.041
  4. ↑ Shanbhag NM, Rafalska-Metcalf IU, Balane-Bolivar C, Janicki SM, Greenberg RA. ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks. Cell. 2010 Jun 11;141(6):970-81. doi: 10.1016/j.cell.2010.04.038. PMID:20550933 doi:10.1016/j.cell.2010.04.038
  5. ↑ Gatti M, Pinato S, Maspero E, Soffientini P, Polo S, Penengo L. A novel ubiquitin mark at the N-terminal tail of histone H2As targeted by RNF168 ubiquitin ligase. Cell Cycle. 2012 Jul 1;11(13):2538-44. doi: 10.4161/cc.20919. Epub 2012 Jul 1. PMID:22713238 doi:10.4161/cc.20919
  6. ↑ Mallette FA, Mattiroli F, Cui G, Young LC, Hendzel MJ, Mer G, Sixma TK, Richard S. RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites. EMBO J. 2012 Feb 28;31(8):1865-78. doi: 10.1038/emboj.2012.47. PMID:22373579 doi:10.1038/emboj.2012.47
  7. ↑ Yan Z, Guo R, Paramasivam M, Shen W, Ling C, Fox D 3rd, Wang Y, Oostra AB, Kuehl J, Lee DY, Takata M, Hoatlin ME, Schindler D, Joenje H, de Winter JP, Li L, Seidman MM, Wang W. A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to the Fanconi anemia DNA repair network. Mol Cell. 2012 Jul 13;47(1):61-75. doi: 10.1016/j.molcel.2012.05.026. Epub 2012, Jun 14. PMID:22705371 doi:10.1016/j.molcel.2012.05.026
  8. ↑ Panier S, Ichijima Y, Fradet-Turcotte A, Leung CC, Kaustov L, Arrowsmith CH, Durocher D. Tandem protein interaction modules organize the ubiquitin-dependent response to DNA double-strand breaks. Mol Cell. 2012 Aug 10;47(3):383-95. doi: 10.1016/j.molcel.2012.05.045. Epub 2012 , Jun 27. PMID:22742833 doi:10.1016/j.molcel.2012.05.045
  9. ↑ Mattiroli F, Vissers JH, van Dijk WJ, Ikpa P, Citterio E, Vermeulen W, Marteijn JA, Sixma TK. RNF168 Ubiquitinates K13-15 on H2A/H2AX to Drive DNA Damage Signaling. Cell. 2012 Sep 14;150(6):1182-95. doi: 10.1016/j.cell.2012.08.005. PMID:22980979 doi:10.1016/j.cell.2012.08.005
  10. ↑ Campbell SJ, Edwards RA, Leung CC, Neculai D, Hodge CD, Dhe-Paganon S, Glover JN. Molecular Insights into the Function of RING Finger (RNF)-containing Proteins hRNF8 and hRNF168 in Ubc13/Mms2-dependent Ubiquitylation. J Biol Chem. 2012 Jul 6;287(28):23900-10. Epub 2012 May 15. PMID:22589545 doi:10.1074/jbc.M112.359653

3l11, resolution 2.12Å

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