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

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

doi:10.1073/pnas.1515354112

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

Journal Article · Tue Nov 17 00:00:00 EST 2015 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1515354112· OSTI ID:1234751

Meng, Xiangzhi ^[1]; Krumm, Brian ^[2]; Li, Yongchao ^[2]; Deng, Junpeng ^[2]; Xiang, Yan ^[1]

Univ. of Texas Health Science Center at San Antonio, San Antonio, TX (United States)
Oklahoma State Univ., Stillwater, OK (United States)

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. Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: NIH; USDOE

OSTI ID:: 1234751

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 48 Vol. 112; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Stress Beyond Translation: Poxviruses and More Liem, Jason; Liu, Jia Viruses, Vol. 8, Issue 6 https://doi.org/10.3390/v8060169	journal	June 2016
Identification of CP77 as the Third Orthopoxvirus SAMD9 and SAMD9L Inhibitor with Unique Specificity for a Rodent SAMD9L Zhang, Fushun; Meng, Xiangzhi; Townsend, Michael B. Journal of Virology, Vol. 93, Issue 12 https://doi.org/10.1128/jvi.00225-19	journal	March 2019
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