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Human poly(ADP-ribose) polymerase 15, macro domain 2 in complex with adenosine-5-diphosphoribose

PDB Code 3KH6 Target Class Poly ADP-ribose polymerase Target PARP15 (macro domain) Alias BAL3, FLJ40196, FLJ40597, MGC126750, MGC126752, PARP15 Disease Area/Function cancer Date Deposited Oct 30 2009 Authors T.KARLBERG, M.MOCHE, C.H.ARROWSMITH, H.BERGLUND, C.BOUNTRA, R.COLLINS, A.M.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, A.JOHANSSON, I.JOHANSSON, A.KALLAS, T.KOTENYOVA, A.KOTZSCH, P.KRAULIS, T.K.NIELSEN, P.NORDLUND, T.NYMAN, C.PERSSON, A.K.ROOS, P.SCHUTZ, M.I.SIPONEN, A.G.THORSELL, L.TRESAUGUES, S.VAN DEN BERG, J.WEIGELT, M.WELIN, M.WISNIEWSKA, H.SCHULER Related Structure 3BLJ, 3GEY

About this structure

Poly(ADP-ribose) polymerases (PARPs) use NAD+ as a substrate to add poly(ADP)ribose (PAR) to other proteins or themselves, leading to a changed three-dimensional and electrostatic surface of the modified proteins (1). PAR is critically involved in genome organization, transcriptional regulation, and DNA repair (2). The human PARP family consists of 17 proteins that all contain a catalytic domain in the context of different domains conferring interactions with other proteins and subcellular localization (3).

PARP-15 belongs to the sub-class of macro-PARPs, including also PARP-9 and PARP-14. These proteins have not been extensively studied but are thought to function as transcription cofactors (4). In addition to a catalytic PARP domain these proteins have up to three macrodomains in their N-terminal part. Macrodomains are small globular domains found in more than 200 bacterial and virus proteins as well as in histone macro H2A-protein in mammals (5,6). Macrodomains bind ADP-ribose with high affinity and selectivity (7) and are recruited to sites of PARP1 activation following DNA damage (8).

Here, the crystal structure of the macrodomain of human PARP-15 is presented in complex with ADP-Ribose at 2.2Å resolution. The structure consists of a seven-stranded mostly parallel β-sheet, except for β1 and β7 that are anti-parallel (strand-order β1-β2-β7-β6-β3-β5-β4), and a total of six α-helices, three on each side of the β-sheet. The overall structure is globular and measures approximately 35Å × 35Å × 50Å. ADP-ribose was clearly seen in the electron density located in a binding cleft mainly made up from two seemingly flexible loops, β3-loop-α2 and β6-loop-α5.

References

  1. Hassa PO and Hottiger MO. (2008) The diverse biological roles of mammalian PARPs, a small but powerful family of poly-ADP-ribose polymerases. Front. Biosci. 13, 3046-3082. PubMed 17981777
  2. Schreiber V et al. (2006) Poly(ADP-ribose): novel functions for an old molecule. Nature Rev. Mol. Cell Biol. 7, 517-528. PubMed 16829982
  3. Amé JC et al. (2004) The PARP superfamily. Bioessays 26, 882-893. PubMed 15273990
  4. Hakmé A et al. (2008) The macroPARP genes Parp-9 and Parp-14 are developmentally and differentially regulated in mouse tissues. Develop. Dynam. 237, 209-215. PubMed 18069692
  5. Gorbalenya AE, Koonin EV and Lai MM-C. (1991) Putative papain-related thiol proteases of positive-strand RNA viruses. FEBS Lett. 288, 201-205. PubMed 1652473
  6. Pehrson JR and Fried VA. (1992) MacroH2A, a core Histone containing a large nonhistone region. Science 257, 1398-1400. PubMed 1529340
  7. Karras GI et al. (2005) The macro domain is an ADP-ribose binding module. EMBO J. 24, 1911-1920. PubMed 15902274
  8. Timinszky G et al. (2009) A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation. Nature Struct. Mol. Biol. 16, 923-929. PubMed 19680243