Structural analyses of NudT16–ADP-ribose complexes direct rational design of mutants with improved processing of poly(ADP-ribosyl)ated proteins

Thirawatananond, Puchong; McPherson, Robert Lyle; Malhi, Jasmine; Nathan, Sara; Lambrecht, Michael J.; Brichacek, Matthew; Hergenrother, Paul J.; Leung, Anthony K. L.; Gabelli, Sandra B.

doi:10.1038/s41598-019-39491-w

Title: Structural analyses of NudT16–ADP-ribose complexes direct rational design of mutants with improved processing of poly(ADP-ribosyl)ated proteins

Journal Article · Thu Apr 11 00:00:00 EDT 2019 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-019-39491-w· OSTI ID:1619471

Thirawatananond, Puchong;

; Malhi, Jasmine;

; Lambrecht, Michael J.;

; Hergenrother, Paul J.;

;

Abstract ADP-ribosylation is a post-translational modification that occurs on chemically diverse amino acids, including aspartate, glutamate, lysine, arginine, serine and cysteine on proteins and is mediated by ADP-ribosyltransferases, including a subset commonly known as poly(ADP-ribose) polymerases. ADP-ribose can be conjugated to proteins singly as a monomer or in polymeric chains as poly(ADP-ribose). While ADP-ribosylation can be reversed by ADP-ribosylhydrolases, this protein modification can also be processed to phosphoribosylation by enzymes possessing phosphodiesterase activity, such as snake venom phosphodiesterase, mammalian ectonucleotide pyrophosphatase/phosphodiesterase 1, Escherichia coli RppH, Legionella pneumophila Sde and Homo sapiens NudT16 ( Hs NudT16). Our studies here sought to utilize X-ray crystallographic structures of Hs NudT16 in complex with monomeric and dimeric ADP-ribose in identifying the active site for binding and processing free and protein-conjugated ADP-ribose into phosphoribose forms. These structural data guide rational design of mutants that widen the active site to better accommodate protein-conjugated ADP-ribose. We identified that several Hs NudT16 mutants (Δ17, F36A, and F61S) have reduced activity for free ADP-ribose, similar processing ability against protein-conjugated mono(ADP-ribose), but improved catalytic efficiency for protein-conjugated poly(ADP-ribose). These Hs NudT16 variants may, therefore, provide a novel tool to investigate different forms of ADP-ribose.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Argonne National Laboratory (ANL), Argonne, IL (United States); Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institute of Health (NIH), Allegheny Health Network–Johns Hopkins Cancer Research Fund; Allegheny Health Network–Johns Hopkins Cancer Research Fund; Johns Hopkins Catalyst Award; American Cancer Society Research Scholar Award; NIH National Institute of General Medical Sciences

Grant/Contract Number:: KP1605010; AC02-05CH11231; AC02-06CH11357; SC0012704; CA062924; R01GM104135; BC151831; RSG-16-062-01-RMC; NRSA 1-T-32- GM070421

OSTI ID:: 1619471

Alternate ID(s):: OSTI ID: 1624458

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Vol. 9 Journal Issue: 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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Cited by: 10 works

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