Structural basis of chemokine sequestration by a herpesvirus decoy receptor.
The M3 protein encoded by murine gamma herpesvirus68 (gamma HV68) functions as an immune system saboteur by the engagement of chemoattractant cytokines, thereby altering host antiviral inflammatory responses. Here we report the crystal structures of M3 both alone and in complex with the CC chemokine MCP-1. M3 is a two-domain beta sandwich protein with a unique sequence and topology, forming a tightly packed anti-parallel dimer. The stoichiometry of the MCP-1:M3 complex is 2:2, with two monomeric chemokines embedded at distal ends of the preassociated M3 dimer. Conformational flexibility and electrostatic complementation are both used by M3 to achieve high-affinity and broad-spectrum chemokine engagement. M3 also employs structural mimicry to promiscuously sequester chemokines, engaging conservative structural elements associated with both chemokine homodimerization and binding to G protein-coupled receptors.
Alexander
Jennifer M
JM
Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Nelson
Christopher A
CA
van Berkel
Victor
V
Lau
Elaine K
EK
Studts
Joey M
JM
Brett
Tom J
TJ
Speck
Samuel H
SH
Handel
Tracy M
TM
Virgin
Herbert W
HW
Fremont
Daved H
DH
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018932:Chemokine CCL2 / Q000737:chemistry*; D019281:Dimerization; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D012996:Solutions; D014764:Viral Proteins / Q000737:chemistry*
D018932:Chemokine CCL2; C118862:M3 protein, Murine gammaherpesvirus; D011991:Receptors, Virus; D012996:Solutions; D014764:Viral Proteins