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Crystal structures and functional analysis of the ZnF5-WWE1-WWE2 region of PARP13/ZAP define a distinctive mode of

Jijin R A Kuttiyatveetil1, Heddy Soufari1, Morgan Dasovich2

  • 1Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada.

Cell Reports
|October 26, 2022
PubMed

Insights

The zinc-finger antiviral protein (PARP13/ZAP) targets viral mRNA. Researchers determined the structure of its central domain, revealing how it binds ADP-ribose and ATP, crucial for its antiviral function.

Area of Science:

  • Structural Biology
  • Virology
  • Biochemistry

Background:

  • The zinc-finger antiviral protein (PARP13/ZAP) is vital for antiviral defense by degrading viral mRNA.
  • PARP13/ZAP possesses distinct structural domains, including N-terminal zinc fingers, a C-terminal ADP ribosyltransferase fold, and a central region (ZnF5-WWE1-WWE2).
  • The precise structure and function of the ZnF5-WWE1-WWE2 region in poly(ADP-ribose) binding remain incompletely understood.

Purpose of the Study:

  • To elucidate the structural basis of poly(ADP-ribose) and ATP binding within the central ZnF5-WWE1-WWE2 region of mouse PARP13/ZAP.
  • To investigate the functional implications of these interactions for PARP13/ZAP's antiviral activity.

Main Methods:

  • X-ray crystallography was employed to determine the structures of the ZnF5-WWE1-WWE2 region in complex with ADP-ribose and ATP.
  • Biochemical binding assays were conducted using various poly(ADP-ribose) ligands to assess binding affinities and specificities.

Main Results:

  • Crystal structures revealed that the WWE2 domain, but not WWE1, directly interacts with ADP-ribose and ATP.
  • Binding studies demonstrated that WWE2 preferentially binds to the terminal end of poly(ADP-ribose) chains.
  • The combined ZnF5-WWE1-WWE2 structure presents an extended surface for poly(ADP-ribose) chain recognition.

Conclusions:

  • The WWE2 domain is the primary site for ADP-ribose and ATP binding within the central region of PARP13/ZAP.
  • PARP13/ZAP utilizes a unique binding mode to recognize poly(ADP-ribose) chains, primarily through its WWE2 domain.
  • These findings provide a structural framework for understanding how poly(ADP-ribose) influences PARP13/ZAP function in antiviral defense.
Keywords:
ADP-riboseATPCP: Molecular biologyPARP13SEC-SAXSWWE domainX-ray crystallographyZAPfluorescence polarizationpoly(ADP-ribose)

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