Macrodomaincontaining

Macrodomain-containing refers to proteins that harbor one or more macrodomain modules, a conserved protein fold that recognizes and, in many cases, processes ADP-ribose and related metabolites. Macrodomains are typically around 180 amino acids in length and form a compact, ligand-binding pocket. Depending on the protein, the macrodomain can act as a binding module that recognizes ADP-ribosylation, or as a catalytic domain that removes mono-ADP-ribose from substrates, or both.

In humans, several macrodomain-containing enzymes function as ADP-ribosylhydrolases, reversing mono-ADP-ribosylation and influencing signaling, DNA repair, and chromatin dynamics. Examples include MACROD1 and MACROD2, which remove mono-ADP-ribose from modified proteins. Other macrodomain proteins contribute to the regulation of transcription and cellular stress responses by reading ADP-ribose marks.

Viruses and bacteria also encode macrodomain-containing proteins. A well-studied example is the macrodomain of coronavirus nonstructural protein 3 (nsp3), which exhibits ADP-ribosylhydrolase activity and can modulate host immune responses by removing ADP-ribose modifications on host or viral proteins.

Macrodomain modules are broadly distributed across bacteria, archaea, eukaryotes, and many viruses, indicating an ancient origin with diversification over evolution. The biological roles of macrodomain-containing proteins span DNA repair, chromatin regulation, metabolism, and immune signaling, making them of interest in disease research and drug development.