Molecular mechanism of poly(ADP-ribosyl)ation by PARP1 and identification of lysine residues as ADP-ribose acceptor sites

Poly(ADP-ribose) polymerase 1 (PARP1) synthesizes poly(ADP-ribose) (PAR) using nicotinamide adenine dinucleotide (NAD) as a substrate. Despite intensive research on the cellular functions of PARP1, the molecular mechanism of PAR formation has not been comprehensively understood. In this study, we el...

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Vydáno v:	Nucleic acids research Ročník 37; číslo 11; s. 3723 - 3738
Hlavní autoři:	Altmeyer, Matthias, Messner, Simon, Hassa, Paul O, Fey, Monika, Hottiger, Michael O
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England Oxford University Press 01.06.2009 Oxford Publishing Limited (England)
Témata:	active sites Adenosine diphosphate Catalytic Domain Cell Cycle Proteins - chemistry Cell Cycle Proteins - metabolism Deoxyribonucleic acid DNA DNA - metabolism DNA-binding domains glutamic acid Glutamic Acid - metabolism Humans lysine Lysine - metabolism NAD (coenzyme) NAD ADP-ribosyltransferase nucleic acids Nucleic Acids Enzymes Poly (ADP-Ribose) Polymerase-1 Poly Adenosine Diphosphate Ribose - metabolism Poly(ADP-ribose) Polymerases - chemistry Poly(ADP-ribose) Polymerases - metabolism Protein Multimerization Protein Structure, Tertiary recombinant fusion proteins
ISSN:	0305-1048, 1362-4962, 1362-4962
On-line přístup:	Získat plný text
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Popis
Shrnutí:	Poly(ADP-ribose) polymerase 1 (PARP1) synthesizes poly(ADP-ribose) (PAR) using nicotinamide adenine dinucleotide (NAD) as a substrate. Despite intensive research on the cellular functions of PARP1, the molecular mechanism of PAR formation has not been comprehensively understood. In this study, we elucidate the molecular mechanisms of poly(ADP-ribosyl)ation and identify PAR acceptor sites. Generation of different chimera proteins revealed that the amino-terminal domains of PARP1, PARP2 and PARP3 cooperate tightly with their corresponding catalytic domains. The DNA-dependent interaction between the amino-terminal DNA-binding domain and the catalytic domain of PARP1 increased Vmax and decreased the Km for NAD. Furthermore, we show that glutamic acid residues in the auto-modification domain of PARP1 are not required for PAR formation. Instead, we identify individual lysine residues as acceptor sites for ADP-ribosylation. Together, our findings provide novel mechanistic insights into PAR synthesis with significant relevance for the different biological functions of PARP family members.
Bibliografie:	istex:19E8DAED79BE8D943A743A42A05C8FB1259128F8 ark:/67375/HXZ-TWH2TDGL-T ArticleID:gkp229 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23
ISSN:	0305-1048 1362-4962 1362-4962
DOI:	10.1093/nar/gkp229