Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis

Abstract

Viruses from the Coronaviridae, Togaviridae, and Hepeviridae families ​all contain genes that encode a conserved protein domain, called a macrodomain; however, the role of this domain during infection has remained enigmatic. The recent discovery that mammalian macrodomain proteins enzymatically remove ADP-ribose, a common post-translation modification, from proteins has led to an outburst of studies describing both the enzymatic activity and function of viral macrodomains. These new studies have defined these domains as de-ADP-ribosylating enzymes, which indicates that these viruses have evolved to counteract antiviral ADP-ribosylation, likely mediated by poly-ADP-ribose polymerases (PARPs). Here, we comprehensively review this rapidly expanding field, describing the structures and enzymatic activities of viral macrodomains, and discussing their roles in viral replication and pathogenesis.

Keywords: ADP-ribosylation; Coronaviridae; Hepeviridae; Togaviridae; interferon (IFN); macrodomain; pathogenesis; poly-ADP-ribose polymerase (PARP); replication.

Figure 1

Removal of ADP-Ribose from Protein by Macrodomains. A schematic representation of de-ADP-ribosylation reaction of proteins modified on acidic residues. Proximal and distal ribose are shaded in gray, α and β phosphate groups are shaded in orange.

Figure 2

Structures and Multiple Sequence Alignment of Viral Macrodomains. (Top left) A conserved surface representation of SARS macrodomain (PDB:2FAV) based on ConSurf analysis. The most conserved residues are coloured in magenta, while the least conserved residues are coloured in cyan. ADP-ribose is shown in stick representation. (Top right) ADP-ribose binding cleft of SARS macrodomain alone (gray) (PDB:2FAV), aligned with CHIKV macrodomain (Middle left, orange) (PDB:3GPO), or human MacroD2 macrodomain (Middle right, salmon) (PDB:4IQY). The proteins are shown as cartoon, with key residues shown as sticks. Loop 1 and loop 2 are coloured in slate and pale-green, respectively (SARS-CoV macrodomain only). (Bottom) Sequence alignment of selected viral and human macrodomains. The name of the virus is indicated on the left. Structure availability is indicated by a Protein Data Bank code; for viral macrodomains where no structural information is available, UniProt retrieved sequences of the macrodomains were used and are indicated as (Seq.). Secondary structure elements are schematically depicted above the alignment, and the numbering is for a generic macrodomain (i.e., not including additional helices or sheets present in some but not all macrodomains). Asterisks and red boxes indicate highly conserved, mostly substituted or key catalytic determinant residues of viral macrodomains. Magenta-shaded boxes depict the degree of conservation.

Figure 3

Genomic Location of Viral Macrodomains. Diagram depicting the genomic locations of macrodomains in the Hepeviridae, Togaviridae, and Coronaviridae. All viral macrodomains are a distinct domain of a larger nonstructural protein, ORF1 in Hepeviridae and nsP3 in both the Togaviridae and Coronaviridae. For Coronaviridae there are multiple macrodomains, listed Mac1/2/3. Mac1 is analogous to macrodomains found in other viruses.