PARP14 is a writer, reader, and eraser of mono-ADP-ribosylation
(2023) In The Journal of biological chemistry 299(9).- Abstract
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 and its three ADP-ribosyl binding macro domains has been regarded as a potential means of therapeutic intervention. Macrodomains-2 and -3 are known to stably bind to ADP-ribosylated target proteins, but the function of macrodomain-1 has remained somewhat elusive. Here, we used biochemical assays of ADP-ribosylation levels to characterize PARP14 macrodomain-1 and the homologous macrodomain-1 of PARP9. Our results show that both macrodomains display an ADP-ribosyl glycohydrolase activity that is not directed toward specific protein side chains. PARP14... (More)
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 and its three ADP-ribosyl binding macro domains has been regarded as a potential means of therapeutic intervention. Macrodomains-2 and -3 are known to stably bind to ADP-ribosylated target proteins, but the function of macrodomain-1 has remained somewhat elusive. Here, we used biochemical assays of ADP-ribosylation levels to characterize PARP14 macrodomain-1 and the homologous macrodomain-1 of PARP9. Our results show that both macrodomains display an ADP-ribosyl glycohydrolase activity that is not directed toward specific protein side chains. PARP14 macrodomain-1 is unable to degrade poly(ADP-ribose), the enzymatic product of PARP1. The F926A mutation of PARP14 and the F244A mutation of PARP9 strongly reduced ADP-ribosyl glycohydrolase activity of the respective macrodomains, suggesting mechanistic homology to the Mac1 domain of the SARS-CoV-2 Nsp3 protein. This study adds two new enzymes to the previously known six human ADP-ribosyl glycohydrolases. Our results have key implications for how PARP14 and PARP9 will be studied and how their functions will be understood.
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- author
- Torretta, Archimede LU ; Chatzicharalampous, Constantinos LU ; Ebenwaldner, Carmen LU and Schüler, Herwig LU
- organization
- publishing date
- 2023-07-26
- type
- Contribution to journal
- publication status
- published
- subject
- in
- The Journal of biological chemistry
- volume
- 299
- issue
- 9
- article number
- 105096
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- scopus:85168310910
- pmid:37507011
- ISSN
- 1083-351X
- DOI
- 10.1016/j.jbc.2023.105096
- project
- Structure-function relationship in ADP-ribosyl transferases
- language
- English
- LU publication?
- yes
- id
- 099ead83-dac1-4379-b152-d853a54b9aa3
- date added to LUP
- 2023-09-28 11:34:46
- date last changed
- 2024-04-19 01:47:04
@article{099ead83-dac1-4379-b152-d853a54b9aa3, abstract = {{<p>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 and its three ADP-ribosyl binding macro domains has been regarded as a potential means of therapeutic intervention. Macrodomains-2 and -3 are known to stably bind to ADP-ribosylated target proteins, but the function of macrodomain-1 has remained somewhat elusive. Here, we used biochemical assays of ADP-ribosylation levels to characterize PARP14 macrodomain-1 and the homologous macrodomain-1 of PARP9. Our results show that both macrodomains display an ADP-ribosyl glycohydrolase activity that is not directed toward specific protein side chains. PARP14 macrodomain-1 is unable to degrade poly(ADP-ribose), the enzymatic product of PARP1. The F926A mutation of PARP14 and the F244A mutation of PARP9 strongly reduced ADP-ribosyl glycohydrolase activity of the respective macrodomains, suggesting mechanistic homology to the Mac1 domain of the SARS-CoV-2 Nsp3 protein. This study adds two new enzymes to the previously known six human ADP-ribosyl glycohydrolases. Our results have key implications for how PARP14 and PARP9 will be studied and how their functions will be understood.</p>}}, author = {{Torretta, Archimede and Chatzicharalampous, Constantinos and Ebenwaldner, Carmen and Schüler, Herwig}}, issn = {{1083-351X}}, language = {{eng}}, month = {{07}}, number = {{9}}, publisher = {{American Society for Biochemistry and Molecular Biology}}, series = {{The Journal of biological chemistry}}, title = {{PARP14 is a writer, reader, and eraser of mono-ADP-ribosylation}}, url = {{http://dx.doi.org/10.1016/j.jbc.2023.105096}}, doi = {{10.1016/j.jbc.2023.105096}}, volume = {{299}}, year = {{2023}}, }