Regulation of ADP-ribosyltransferase activity by ART domain dimerization in PARP15 DOI Open Access
Carmen Ebenwaldner,

Antonio Ginés García Saura,

Simon Ekström

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 4, 2024

Abstract PARP15 is a mono-ADP-ribosyltransferase with unknown functions. Its evolutionary relationship PARP14 suggests roles in antiviral defense; its ability to modify RNA and localization stress granules point functions the regulation of translation. also modifies itself other proteins using ADP-ribosyltransferase (ART) domain contains two macrodomains predicted bind ADP-ribosyl on targets. We used biochemical biophysical analysis study how activity regulated. Here we show that catalytic dimerizes mid-nanomolar affinity, forming same dimer interface solution had already been captured by X-ray crystallography domain. Furthermore, formation dimers prerequisite for monomeric mutant variants were catalytically inactive. Our findings suggest regulatory mechanism which dimerization linked either target engagement or placement residue, rather than NAD+ co-substrate binding, protomers operate independent one another. Together, our results uncover novel PARP family enzyme, might inspire new avenues pharmacological intervention.

Язык: Английский

ADP-ribosylation from molecular mechanisms to therapeutic implications DOI Creative Commons
Marcin J. Suskiewicz, Evgeniia Prokhorova, J.G.M. Rack

и другие.

Cell, Год журнала: 2023, Номер 186(21), С. 4475 - 4495

Опубликована: Окт. 1, 2023

ADP-ribosylation is a ubiquitous modification of biomolecules, including proteins and nucleic acids, that regulates various cellular functions in all kingdoms life. The recent emergence new technologies to study has reshaped our understanding the molecular mechanisms govern establishment, removal, recognition this modification, as well its impact on organismal function. These advances have also revealed intricate involvement human physiology pathology enormous potential their manipulation holds for therapy. In review, we present state-of-the-art findings covering work structural biology, biochemistry, cell clinical aspects ADP-ribosylation.

Язык: Английский

Процитировано

70
PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation DOI

Pulak Kar,

Chatrin Chatrin, N Mimica Dukic

и другие.

The EMBO Journal, Год журнала: 2024, Номер 43(14), С. 2929 - 2953

Опубликована: Июнь 4, 2024

Язык: Английский

Процитировано

16
Parps in immune response: Potential targets for cancer immunotherapy DOI

S Wang,

Jingling Huang,

T. X. Zeng

и другие.

Biochemical Pharmacology, Год журнала: 2025, Номер 234, С. 116803 - 116803

Опубликована: Фев. 16, 2025

Язык: Английский

Процитировано

2
PARP14 is a writer, reader, and eraser of mono-ADP-ribosylation DOI Creative Commons
Archimede Torretta, Constantinos Chatzicharalampous, Carmen Ebenwaldner

и другие.

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(9), С. 105096 - 105096

Опубликована: Июль 26, 2023

PARP14/BAL2 is a large multidomain enzyme involved in signaling pathways with relevance to cancer, inflammation, and infection. Inhibition of its mono-ADP-ribosylating PARP homology domain three ADP-ribosyl binding macro domains has been regarded as potential means therapeutic intervention. Macrodomains-2 -3 are known stably bind ADP-ribosylated target proteins, but the function macrodomain-1 remained somewhat elusive. Here, we used biochemical assays ADP-ribosylation levels characterize PARP14 homologous PARP9. Our results show that both macrodomains display an glycohydrolase activity not directed toward specific protein side chains. unable degrade poly(ADP-ribose), enzymatic product PARP1. The F926A mutation F244A PARP9 strongly reduced respective macrodomains, suggesting mechanistic Mac1 SARS-CoV-2 Nsp3 protein. This study adds two new enzymes previously six human glycohydrolases. have key implications for how will be studied their functions understood.

Язык: Английский

Процитировано

24
DELTEX E3 ligases ubiquitylate ADP-ribosyl modification on nucleic acids DOI Creative Commons
Kang Zhu, Marcin J. Suskiewicz, Chatrin Chatrin

и другие.

Nucleic Acids Research, Год журнала: 2023, Номер 52(2), С. 801 - 815

Опубликована: Ноя. 24, 2023

Abstract Although ubiquitylation had traditionally been considered limited to proteins, the discovery of non-proteinaceous substrates (e.g. lipopolysaccharides and adenosine diphosphate ribose (ADPr)) challenged this perspective. Our recent study showed that DTX2 E3 ligase efficiently ubiquitylates ADPr. Here, we show ADPr activity is also present in another DELTEX family member, DTX3L, analysed both as an isolated catalytic fragment full-length PARP9:DTX3L complex, suggesting it a general feature family. Since structural predictions DTX3L possesses single-stranded nucleic acids binding ability given fact have recently emerged for ADP-ribosylation, asked whether E3s might catalyse moiety linked acids. Indeed, are capable ubiquitylating ADP-ribosylated DNA RNA synthesized by PARPs, including PARP14. Furthermore, demonstrate Ub-ADPr-nucleic conjugate can be reversed two groups hydrolases, which remove either whole adduct SARS-CoV-2 Mac1 or PARP14 macrodomain 1) just Ub PLpro). Overall, reveals function presents evidence reversible

Язык: Английский

Процитировано

24
The logic of protein post‐translational modifications (PTMs): Chemistry, mechanisms and evolution of protein regulation through covalent attachments DOI Creative Commons
Marcin J. Suskiewicz

BioEssays, Год журнала: 2024, Номер 46(3)

Опубликована: Янв. 21, 2024

Abstract Protein post‐translational modifications (PTMs) play a crucial role in all cellular functions by regulating protein activity, interactions and half‐life. Despite the enormous diversity of modifications, various PTM systems show parallels their chemical catalytic underpinnings. Here, focussing on that involve addition new elements to amino‐acid sidechains, I describe historical milestones fundamental concepts support current understanding PTMs. The survey covers selected key research programmes, including study phosphorylation as regulatory switch, ubiquitylation degradation signal histone functional code. contribution techniques for studying PTMs is also discussed. central part essay explores shared principles strategies observed across diverse systems, together with mechanisms substrate selection, reversibility erasers recognition reader domains. Similarities basic mechanism are highlighted implications final dedicated evolutionary trajectories beginning possible emergence context rivalry prokaryotic world. Together, provides unified perspective world major modifications.

Язык: Английский

Процитировано

9
PARP14 is regulated by the PARP9/DTX3L complex and promotes interferon γ-induced ADP-ribosylation DOI
Victória Chaves Ribeiro, Lilian C. Russo, Nícolas C. Hoch

и другие.

The EMBO Journal, Год журнала: 2024, Номер 43(14), С. 2908 - 2928

Опубликована: Июнь 4, 2024

Язык: Английский

Процитировано

9
Mutation of a highly conserved isoleucine residue in loop 2 of several 𝛽-coronavirus macrodomains indicates that enhanced ADP-ribose binding is detrimental to infection DOI Creative Commons
Catherine M. Kerr, Jessica J. Pfannenstiel, Yousef M. Alhammad

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 4, 2024

All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in nonstructural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown important virus replication pathogenesis. Within Mac1, there are several regions highly across CoVs, including the GIF (glycine-isoleucine-phenylalanine) motif. To determine how biochemical activities of these residues impact CoV replication, isoleucine phenylalanine were mutated to alanine (I-A/F-A) both recombinant proteins murine hepatitis (MHV), Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute 2 (SARS-CoV-2). The F-A mutant had ADP-ribose binding and/or hydrolysis defects led attenuated pathogenesis cell culture mice. In contrast, I-A mutations normal enzyme activity enhanced binding. Despite increased binding, MERS-CoV SARS-CoV-2 mice, indicating this residue acts as gate controls efficient replication. These results highlight function provide unique insight into macrodomains control promote viral

Язык: Английский

Процитировано

6
PARP14 is pro- and anti-viral host factor that promotes IFN production and affects the replication of multiple viruses DOI

Srivatsan Parthasarathy,

Pradtahna Saenjamsai,

Hongping Hao

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 26, 2024

ABSTRACT PARP14 is a 203 kDa multi-domain protein that primarily known as an ADP-ribosyltransferase, and involved in variety of cellular functions including DNA damage, microglial activation, inflammation, cancer progression. In addition, upregulated by interferon (IFN), indicating role the antiviral response. Furthermore, has evolved under positive selection, again it host-pathogen conflict. We found required for increased IFN-I production response to coronavirus infection lacking ADP-ribosylhydrolase (ARH) activity poly(I:C), however, whether direct function remains unclear. Here we demonstrate catalytic enhances IFN-III responses restricts ARH-deficient murine hepatitis virus (MHV) severe acute respiratory syndrome 2 (SARS-CoV-2) replication. To determine if PARP14’s extended beyond CoVs, tested ability herpes simplex 1 (HSV-1) several negative-sense RNA viruses, vesicular stomatitis (VSV), Ebola (EBOV), Nipah (NiV), infect A549 knockout (KO) cells. HSV-1 had replication KO cells, contrast, was critical efficient VSV, EBOV, NiV, with EBOV infectivity at less than 1% WT A active site inhibitor no impact on or infection, its effect these viruses independent activity. These data promotes IFN both pro– anti-viral targeting multiple viruses. IMPORTANCE The largely regulated post-translation modifications (PTM), ADP-ribosylation. ADP-ribosyltransferase However, been described PARP14. Here, represses replication, demonstrating functions. Surprisingly, also pro-viral functions, which have high mortality are pandemic potential. indicate potential therapeutic target highly pathogenic

Язык: Английский

Процитировано

6
Specificity of DNA ADP-Ribosylation Reversal by NADARs DOI Creative Commons
Bara Cihlova, Yang Lu,

Andreja Mikoč

и другие.

Toxins, Год журнала: 2024, Номер 16(5), С. 208 - 208

Опубликована: Апрель 28, 2024

Recent discoveries establish DNA and RNA as bona fide substrates for ADP-ribosylation. NADAR (“NAD- ADP-ribose”-associated) enzymes reverse guanine ADP-ribosylation serve antitoxins in the DarT-NADAR operon. Although NADARs are widespread across prokaryotes, eukaryotes, viruses, their specificity broader physiological roles remain poorly understood. Using phylogenetic biochemical analyses, we further explore de-ADP-ribosylation activity antitoxin functions of domains. We demonstrate that different subfamilies proteins from representative E. coli strains an coli-infecting phage retain while displaying providing protection toxic cells. Furthermore, identify a myxobacterial enzyme within YbiA subfamily its associated DarT-unrelated ART toxin, which termed YarT, thus presenting hitherto uncharacterised ART-YbiA toxin–antitoxin pair. Our studies contribute to burgeoning field ADP-ribosylation, supporting relevance beyond bacterial systems. Notably, confinement non-mammals infer potential highly specific targets antimicrobial drugs with minimal off-target effects.

Язык: Английский

Процитировано

4