Structure of Human ADP-ribosyl-acceptor Hydrolase 3 Bound to ADP-ribose Reveals a Conformational Switch That Enables Specific Substrate Recognition

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2018 Jun 17

PMID 29907568

Citations 22

Authors

Yasin Pourfarjam

Jessica Ventura

Igor Kurinov

Ahra Cho

Joel Moss

In-Kwon Kim

Affiliations

Soon will be listed here.

Abstract

ADP-ribosyl-acceptor hydrolase 3 (ARH3) plays important roles in regulation of poly(ADP-ribosyl)ation, a reversible post-translational modification, and in maintenance of genomic integrity. ARH3 degrades poly(ADP-ribose) to protect cells from poly(ADP-ribose)-dependent cell death, reverses serine mono(ADP-ribosyl)ation, and hydrolyzes -acetyl-ADP-ribose, a product of Sirtuin-catalyzed histone deacetylation. ARH3 preferentially hydrolyzes -linkages attached to the anomeric C1″ of ADP-ribose; however, how ARH3 specifically recognizes and cleaves structurally diverse substrates remains unknown. Here, structures of full-length human ARH3 bound to ADP-ribose and Mg, coupled with computational modeling, reveal a dramatic conformational switch from closed to open states that enables specific substrate recognition. The glutamate flap, which blocks substrate entrance to Mg in the unliganded closed state, is ejected from the active site when substrate is bound. This closed-to-open transition significantly widens the substrate-binding channel and precisely positions the scissile 1″--linkage for cleavage while securing tightly 2″- and 3″-hydroxyls of ADP-ribose. Our collective data uncover an unprecedented structural plasticity of ARH3 that supports its specificity for the 1″--linkage in substrates and Mg-dependent catalysis.

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References

Tucker J, Bennett N, Brassington C, Durant S, Hassall G, Holdgate G . Structures of the human poly (ADP-ribose) glycohydrolase catalytic domain confirm catalytic mechanism and explain inhibition by ADP-HPD derivatives. PLoS One. 2012; 7(12):e50889. PMC: 3519477. DOI: 10.1371/journal.pone.0050889. View

Rosenthal F, Feijs K, Frugier E, Bonalli M, Forst A, Imhof R . Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases. Nat Struct Mol Biol. 2013; 20(4):502-7. DOI: 10.1038/nsmb.2521. View

Otwinowski Z, Minor W . Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 1997; 276:307-26. DOI: 10.1016/S0076-6879(97)76066-X. View

Yu S, Andrabi S, Wang H, Kim N, Poirier G, Dawson T . Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc Natl Acad Sci U S A. 2006; 103(48):18314-9. PMC: 1838748. DOI: 10.1073/pnas.0606528103. View

Oka S, Kato J, Moss J . Identification and characterization of a mammalian 39-kDa poly(ADP-ribose) glycohydrolase. J Biol Chem. 2005; 281(2):705-13. DOI: 10.1074/jbc.M510290200. View

Kabsch W, Sander C . Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers. 1983; 22(12):2577-637. DOI: 10.1002/bip.360221211. View

Bonfiglio J, Fontana P, Zhang Q, Colby T, Gibbs-Seymour I, Atanassov I . Serine ADP-Ribosylation Depends on HPF1. Mol Cell. 2017; 65(5):932-940.e6. PMC: 5344681. DOI: 10.1016/j.molcel.2017.01.003. View

Vagin A, Teplyakov A . Molecular replacement with MOLREP. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 1):22-5. DOI: 10.1107/S0907444909042589. View

Palazzo L, Leidecker O, Prokhorova E, Dauben H, Matic I, Ahel I . Serine is the major residue for ADP-ribosylation upon DNA damage. Elife. 2018; 7. PMC: 5837557. DOI: 10.7554/eLife.34334. View

10.

Jankevicius G, Hassler M, Golia B, Rybin V, Zacharias M, Timinszky G . A family of macrodomain proteins reverses cellular mono-ADP-ribosylation. Nat Struct Mol Biol. 2013; 20(4):508-14. PMC: 7097781. DOI: 10.1038/nsmb.2523. View

11.

Winn M, Ballard C, Cowtan K, Dodson E, Emsley P, Evans P . Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 4):235-42. PMC: 3069738. DOI: 10.1107/S0907444910045749. View

12.

Gibson B, Kraus W . New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol. 2012; 13(7):411-24. DOI: 10.1038/nrm3376. View

13.

Megnin-Chanet F, Bollet M, Hall J . Targeting poly(ADP-ribose) polymerase activity for cancer therapy. Cell Mol Life Sci. 2010; 67(21):3649-62. PMC: 2955921. DOI: 10.1007/s00018-010-0490-8. View

14.

Bieche I, Pennaneach V, Driouch K, Vacher S, Zaremba T, Susini A . Variations in the mRNA expression of poly(ADP-ribose) polymerases, poly(ADP-ribose) glycohydrolase and ADP-ribosylhydrolase 3 in breast tumors and impact on clinical outcome. Int J Cancer. 2013; 133(12):2791-800. DOI: 10.1002/ijc.28304. View

15.

Hakme A, Wong H, Dantzer F, Schreiber V . The expanding field of poly(ADP-ribosyl)ation reactions. 'Protein Modifications: Beyond the Usual Suspects' Review Series. EMBO Rep. 2008; 9(11):1094-100. PMC: 2581850. DOI: 10.1038/embor.2008.191. View

16.

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

17.

Finch K, Knezevic C, Nottbohm A, Partlow K, Hergenrother P . Selective small molecule inhibition of poly(ADP-ribose) glycohydrolase (PARG). ACS Chem Biol. 2012; 7(3):563-70. PMC: 3306470. DOI: 10.1021/cb200506t. View

18.

Andrabi S, Kim N, Yu S, Wang H, Koh D, Sasaki M . Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci U S A. 2006; 103(48):18308-13. PMC: 1838747. DOI: 10.1073/pnas.0606526103. View

19.

Beck C, Robert I, Reina-San-Martin B, Schreiber V, Dantzer F . Poly(ADP-ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3. Exp Cell Res. 2014; 329(1):18-25. DOI: 10.1016/j.yexcr.2014.07.003. View

20.

Berthold C, Wang H, Nordlund S, Hogbom M . Mechanism of ADP-ribosylation removal revealed by the structure and ligand complexes of the dimanganese mono-ADP-ribosylhydrolase DraG. Proc Natl Acad Sci U S A. 2009; 106(34):14247-52. PMC: 2732831. DOI: 10.1073/pnas.0905906106. View