Crystal structure of human cytomegalovirus IL-10 bound to soluble human IL-10R1.
Human IL-10 (hIL-10) modulates critical immune and inflammatory responses by way of interactions with its high- (IL-10R1) and low-affinity (IL-10R2) cell surface receptors. Human cytomegalovirus exploits the IL-10 signaling pathway by expressing a functional viral IL-10 homolog (cmvIL-10), which shares only 27% sequence identity with hIL-10 yet signals through IL-10R1 and IL-10R2. To define the molecular basis of this virus-host interaction, we determined the 2.7-A crystal structure of cmvIL-10 bound to the extracellular fragment of IL-10R1 (sIL-10R1). The structure reveals cmvIL-10 forms a disulfide-linked homodimer that binds two sIL-10R1 molecules. Although cmvIL-10 and hIL-10 share similar intertwined topologies and sIL-10R1 binding sites, their respective interdomain angles differ by approximately 40 degrees. This difference results in a striking re-organization of the IL-10R1s in the putative cell surface complex. Solution binding studies show cmvIL-10 and hIL-10 share essentially identical affinities for sIL-10R1 whereas the Epstein-Barr virus IL-10 homolog (ebvIL-10), whose structure is highly similar to hIL-10, exhibits a approximately 20-fold reduction in sIL-10R1 affinity. Our results suggest cmvIL-10 and ebvIL-10 have evolved different molecular mechanisms to engage the IL-10 receptors that ultimately enhance the respective ability of their virus to escape immune detection.
Jones
Brandi C
BC
Center for Biophysical Sciences and Engineering, Department of Microbiology, University of Alabama, 1025 18th Street South, Birmingham, AL 35294, USA.
Logsdon
Naomi J
NJ
Josephson
Kristopher
K
Cook
Jennifer
J
Barry
Peter A
PA
Walter
Mark R
MR
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003587:Cytomegalovirus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000737:chemistry* / Q000235:genetics; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000235:genetics; D053701:Receptors, Interleukin-10; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D012995:Solubility
D046911:Macromolecular Substances; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D011994:Recombinant Proteins; D016753:Interleukin-10