title: Structural basis for antagonizing a host restriction factor by C7 family of poxvirus host-range proteins.
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.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229;
authors.forename: Xiangzhi
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Biochemistry and Molecular biology, Oklahoma State University, Stillwater, OK 74078.
authors.forename: Brian
authors.initials: B
authors.lastname: Krumm
authors.affiliation: Department of Biochemistry and Molecular biology, Oklahoma State University, Stillwater, OK 74078.
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular biology, Oklahoma State University, Stillwater, OK 74078 Junpeng.deng@okstate.edu XiangY@uthscsa.edu.
authors.forename: Junpeng
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; Junpeng.deng@okstate.edu XiangY@uthscsa.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiang
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009233:Myxoma virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014616:Vaccinia virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C514443:SAMD9 protein, human; D014764:Viral Proteins
keywords: C7L; SAMD9; crystal structure; host-range factors; poxvirus