Molecular basis for the MacroD1-mediated hydrolysis of ADP-ribosylation

DNA Repair (Amst). 2020 Oct:94:102899. doi: 10.1016/j.dnarep.2020.102899. Epub 2020 Jun 22.

Abstract

MacroD1 is an enzyme that hydrolyzes protein mono-ADP-ribosylation. However, the key catalytic residues of MacroD1 in these biochemical reactions remain elusive. Here, we present the crystal structure of MacroD1 in a complex with ADP-ribose (ADPR). The β5-α10-loop functions as a switch loop to mediate substrate recognition and right orientation. The conserved Phe272 in the β5-α10-loop plays a crucial role in the orientation of ADPR distal ribose, and a conserved hydrogen-bond network contributes significantly to hold and orient the catalytic water12, which mediates ADPR hydrolysis. Moreover, we found that MacroD1 was recruited to the sites of DNA damage via recognition of ADP-ribosylation at DNA lesions. The MacroD1-mediated ADPR hydrolysis is essential for DNA damage repair. Taken together, our study provides structural and functional insights into the molecular mechanism of MacroD1-mediated ADPR hydrolysis and its role in DNA damage repair.

Keywords: ADP-ribosylation; ADPR; Crystal structure; DNA damage repair; MacroD1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate Ribose / metabolism*
  • Amino Acid Sequence
  • Carboxylic Ester Hydrolases / chemistry
  • Carboxylic Ester Hydrolases / metabolism*
  • Catalytic Domain*
  • Crystallography, X-Ray
  • DNA Damage
  • DNA Repair*
  • Humans
  • Hydrogen Bonding
  • Hydrolysis
  • Models, Molecular*
  • Protein Conformation
  • Sequence Alignment

Substances

  • Adenosine Diphosphate Ribose
  • Carboxylic Ester Hydrolases
  • MACROD1 protein, human