Structural basis for lack of ADP-ribosyltransferase activity in poly(ADP-ribose) polymerase-13/zinc finger antiviral protein
Karlberg, Tobias LU ; Klepsch, Mirjam ; Thorsell, Ann-Gerd ; Andersson, C David ; Linusson, Anna and Schüler, Herwig LU
(2015)
In The Journal of biological chemistry
290(12).
p.44-7336
- Abstract
The mammalian poly(ADP-ribose) polymerase (PARP) family includes ADP-ribosyltransferases with diphtheria toxin homology (ARTD). Most members have mono-ADP-ribosyltransferase activity. PARP13/ARTD13, also called zinc finger antiviral protein, has roles in viral immunity and microRNA-mediated stress responses. PARP13 features a divergent PARP homology domain missing a PARP consensus sequence motif; the domain has enigmatic functions and apparently lacks catalytic activity. We used x-ray crystallography, molecular dynamics simulations, and biochemical analyses to investigate the structural requirements for ADP-ribosyltransferase activity in human PARP13 and two of its functional partners in stress granules: PARP12/ARTD12, and... (More)
The mammalian poly(ADP-ribose) polymerase (PARP) family includes ADP-ribosyltransferases with diphtheria toxin homology (ARTD). Most members have mono-ADP-ribosyltransferase activity. PARP13/ARTD13, also called zinc finger antiviral protein, has roles in viral immunity and microRNA-mediated stress responses. PARP13 features a divergent PARP homology domain missing a PARP consensus sequence motif; the domain has enigmatic functions and apparently lacks catalytic activity. We used x-ray crystallography, molecular dynamics simulations, and biochemical analyses to investigate the structural requirements for ADP-ribosyltransferase activity in human PARP13 and two of its functional partners in stress granules: PARP12/ARTD12, and PARP15/BAL3/ARTD7. The crystal structure of the PARP homology domain of PARP13 shows obstruction of the canonical active site, precluding NAD(+) binding. Molecular dynamics simulations indicate that this closed cleft conformation is maintained in solution. Introducing consensus side chains in PARP13 did not result in 3-aminobenzamide binding, but in further closure of the site. Three-dimensional alignment of the PARP homology domains of PARP13, PARP12, and PARP15 illustrates placement of PARP13 residues that deviate from the PARP family consensus. Introducing either one of two of these side chains into the corresponding positions in PARP15 abolished PARP15 ADP-ribosyltransferase activity. Taken together, our results show that PARP13 lacks the structural requirements for ADP-ribosyltransferase activity.
(Less)
- author
- Karlberg, Tobias
LU
; Klepsch, Mirjam
; Thorsell, Ann-Gerd
; Andersson, C David
; Linusson, Anna
and Schüler, Herwig
LU
- publishing date
- 2015-03-20
- type
- Contribution to journal
- publication status
- published
- keywords
- ADP Ribose Transferases/metabolism, Amino Acid Sequence, Crystallography, X-Ray, Humans, Molecular Dynamics Simulation, Molecular Sequence Data, Mutagenesis, Site-Directed, NAD/metabolism, Poly(ADP-ribose) Polymerases/chemistry, Sequence Homology, Amino Acid, Zinc Fingers
- in
- The Journal of biological chemistry
- volume
- 290
- issue
- 12
- pages
- 9 pages
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- pmid:25635049
- scopus:84925310791
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M114.630160
- language
- English
- LU publication?
- no
- additional info
- © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
- id
- 3792f12e-a7bd-426e-a34d-8bd0865e788a
- date added to LUP
- 2024-11-21 17:54:41
- date last changed
- 2025-06-07 08:54:29
@article{3792f12e-a7bd-426e-a34d-8bd0865e788a,
abstract = {{<p>The mammalian poly(ADP-ribose) polymerase (PARP) family includes ADP-ribosyltransferases with diphtheria toxin homology (ARTD). Most members have mono-ADP-ribosyltransferase activity. PARP13/ARTD13, also called zinc finger antiviral protein, has roles in viral immunity and microRNA-mediated stress responses. PARP13 features a divergent PARP homology domain missing a PARP consensus sequence motif; the domain has enigmatic functions and apparently lacks catalytic activity. We used x-ray crystallography, molecular dynamics simulations, and biochemical analyses to investigate the structural requirements for ADP-ribosyltransferase activity in human PARP13 and two of its functional partners in stress granules: PARP12/ARTD12, and PARP15/BAL3/ARTD7. The crystal structure of the PARP homology domain of PARP13 shows obstruction of the canonical active site, precluding NAD(+) binding. Molecular dynamics simulations indicate that this closed cleft conformation is maintained in solution. Introducing consensus side chains in PARP13 did not result in 3-aminobenzamide binding, but in further closure of the site. Three-dimensional alignment of the PARP homology domains of PARP13, PARP12, and PARP15 illustrates placement of PARP13 residues that deviate from the PARP family consensus. Introducing either one of two of these side chains into the corresponding positions in PARP15 abolished PARP15 ADP-ribosyltransferase activity. Taken together, our results show that PARP13 lacks the structural requirements for ADP-ribosyltransferase activity.</p>}},
author = {{Karlberg, Tobias and Klepsch, Mirjam and Thorsell, Ann-Gerd and Andersson, C David and Linusson, Anna and Schüler, Herwig}},
issn = {{1083-351X}},
keywords = {{ADP Ribose Transferases/metabolism; Amino Acid Sequence; Crystallography, X-Ray; Humans; Molecular Dynamics Simulation; Molecular Sequence Data; Mutagenesis, Site-Directed; NAD/metabolism; Poly(ADP-ribose) Polymerases/chemistry; Sequence Homology, Amino Acid; Zinc Fingers}},
language = {{eng}},
month = {{03}},
number = {{12}},
pages = {{44--7336}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
series = {{The Journal of biological chemistry}},
title = {{Structural basis for lack of ADP-ribosyltransferase activity in poly(ADP-ribose) polymerase-13/zinc finger antiviral protein}},
url = {{http://dx.doi.org/10.1074/jbc.M114.630160}},
doi = {{10.1074/jbc.M114.630160}},
volume = {{290}},
year = {{2015}},
}