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

Scientific Reports
Puchong ThirawatananondSandra B Gabelli

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 (HsNudT16). Our studies here sought to utilize X-ray crystallographic structures of HsNudT16 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 HsNudT16 mutants (Δ17, F36A, and F61S) have reduced activity...Continue Reading

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Citations

May 21, 2020·Nucleic Acids Research·Sunny SharmaMegerditch Kiledjian
Oct 14, 2020·Biochemistry. Biokhimii︠a︡·V A Kulikova, A A Nikiforov
Jun 3, 2021·RNA Biology·Wei ZhouDelin Zhang
Dec 21, 2019·Journal of Proteome Research·Robert Lyle McPhersonAnthony K L Leung

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Methods Mentioned

BETA
Assay
size-exclusion chromatography
co-crystallization
X-ray

Software Mentioned

ImageJ
Coot
CCP4
Molprobity
PISA
GraphPad Prism

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