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

  • 2009-04-18
Published in:
  • Nucleic acids research. - 2009
Catalytic Domain
Cell Cycle Proteins
DNA
Glutamic Acid
Humans
Lysine
Poly (ADP-Ribose) Polymerase-1
Poly Adenosine Diphosphate Ribose
Poly(ADP-ribose) Polymerases
Protein Multimerization
Protein Structure, Tertiary
English 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 V(max) and decreased the K(m) 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.
Language
  • English
Open access status
gold
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Persistent URL
https://sonar.ch/global/documents/4356
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