Structural Conservation and Functional Diversity of the Poxvirus Immune Evasion (PIE) Domain Superfamily.
Poxviruses encode a broad array of proteins that serve to undermine host immune defenses. Structural analysis of four of these seemingly unrelated proteins revealed the recurrent use of a conserved beta-sandwich fold that has not been observed in any eukaryotic or prokaryotic protein. Herein we propose to call this unique structural scaffolding the PIE (Poxvirus Immune Evasion) domain. PIE domain containing proteins are abundant in chordopoxvirinae, with our analysis identifying 20 likely PIE subfamilies among 33 representative genomes spanning 7 genera. For example, cowpox strain Brighton Red appears to encode 10 different PIEs: vCCI, A41, C8, M2, T4 (CPVX203), and the SECRET proteins CrmB, CrmD, SCP-1, SCP-2, and SCP-3. Characterized PIE proteins all appear to be nonessential for virus replication, and all contain signal peptides for targeting to the secretory pathway. The PIE subfamilies differ primarily in the number, size, and location of structural embellishments to the beta-sandwich core that confer unique functional specificities. Reported ligands include chemokines, GM-CSF, IL-2, MHC class I, and glycosaminoglycans. We expect that the list of ligands and receptors engaged by the PIE domain will grow as we come to better understand how this versatile structural architecture can be tailored to manipulate host responses to infection.
Department of Pathology and Immunology, Washington University School of Medicine,  St. Louis, MO 63110, USA. nelson@wustl.edu.
Christopher A
CA
Nelson
Department of Pathology and Immunology, Washington University School of Medicine,  St. Louis, MO 63110, USA. mepperson@path.wustl.edu.
Megan L
ML
Epperson
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA. sukrit.singh@wustl.edu.
Sukrit
S
Singh
Department of Pathology and Immunology, Washington University School of Medicine,  St. Louis, MO 63110, USA. jieliott@wustl.edu.
Jabari I
JI
Elliott
Department of Pathology and Immunology, Washington University School of Medicine,  St. Louis, MO 63110, USA. fremont@wustl.edu.|Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA. fremont@wustl.edu.|Department of Molecular Microbiology,Washington University School of Medicine, St. Louis, MO 63110, USA. fremont@wustl.edu.
Daved H
DH
Fremont
D057131:Immune Evasion; D011212:Poxviridae / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*
D014764:Viral Proteins
PIE domain; SECRET domain; chemokine and cytokine decoy receptors; poxvirus; viral immune evasion