Structural basis for antagonizing a host restriction factor by C7 family of poxvirus host-range proteins

Xiangzhi Meng, Brian Krumm, Yongchao Li, Junpeng Deng, Yan Xiang

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Human sterile alpha motif domain-containing 9 (SAMD9) protein is a host restriction factor for poxviruses, but it can be overcome by some poxvirus host-range proteins that share homology with vaccinia virus C7 protein. To understand the mechanism of action for this important family of host-range factors, we determined the crystal structures of C7 and myxoma virus M64, a C7 family member that is unable to antagonize SAMD9. Despite their different functions and only 23% sequence identity, the two proteins have very similar overall structures, displaying a previously unidentified fold comprised of a compact 12-stranded antiparallel β-sandwich wrapped in two short α helices. Extensive structure-guided mutagenesis of C7 identified three loops clustered on one edge of the β sandwich as critical for viral replication and binding with SAMD9. The loops are characterized with functionally important negatively charged, positively charged, and hydrophobic residues, respectively, together forming a unique "three-fingered molecular claw." The key residues of the claw are not conserved in two C7 family members that do not antagonize SAMD9 but are conserved in distantly related C7 family members from four poxvirus genera that infect diverse mammalian species. Indeed, we found that all in the latter group of proteins bind SAMD9. Taken together, our data indicate that diverse mammalian poxviruses use a conserved molecular claw in a C7-like protein to target SAMD9 and overcome host restriction.

Original languageEnglish (US)
Pages (from-to)14858-14863
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number48
DOIs
StatePublished - Dec 1 2015

Keywords

  • C7L
  • Crystal structure
  • Host-range factors
  • Poxvirus
  • SAMD9

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Structural basis for antagonizing a host restriction factor by C7 family of poxvirus host-range proteins'. Together they form a unique fingerprint.

Cite this