General ADP-Ribosylation Mechanism Based on the Structure of ADP-Ribosyltransferase-Substrate Complexes.

Area of Science:

• Biochemistry
• Molecular Biology
• Cellular Biology

Background:

• ADP-ribosylation (ADPR) is a crucial post-translational modification regulating diverse cellular processes across all life forms.
• ADP-ribosyltransferases (ARTs) catalyze ADPR, modifying various substrates and atoms, with their structures and cofactors (NAD+) elucidated.
• Despite decades of research, the precise molecular mechanisms governing ART substrate specificity remain largely unknown.

Purpose of the Study:

• To provide an updated overview of the general ADP-ribosylation mechanism.
• To highlight the importance of tripartite complex structures (ART, cofactor, substrate) in understanding ART function.
• To bridge the knowledge gap regarding how ARTs achieve target specificity.

Main Methods:

• Review of existing structural data of ADP-ribosyltransferases (ARTs) in complex with cofactors (NAD+ or analogs).
• Analysis of structural information pertaining to the tripartite complex, including ART, cofactor, and substrate interactions.
• Synthesis of current understanding of ADP-ribosylation mechanisms based on available structural evidence.

Main Results:

• ARTs exhibit diverse substrate and atom modification capabilities.
• Structural insights into ART-cofactor complexes are available, but tripartite complex structures are crucial for mechanistic understanding.
• The tripartite complex is identified as essential for deciphering the molecular basis of ART action.

Conclusions:

• Understanding the tripartite complex structure is paramount for elucidating the molecular mechanisms of ADP-ribosyltransferases.
• Further structural studies of ART-cofactor-substrate complexes are needed to fully comprehend ADP-ribosylation specificity.
• This review consolidates current knowledge, emphasizing structural biology's role in advancing ADP-ribosylation research.