Structure and immunomodulatory property relationship in NapA of Borrelia burgdorferi.
NapA from Borrelia burgdorferi is a member of the Dps-like protein family with specific immunomodulatory properties; in particular, NapA is able to induce the expression of IL-23 in neutrophils and monocytes, as well as the expression of IL-6, IL-1β, and transforming growth factor beta (TGF-β) in monocytes, via Toll-like receptor (TLR) 2. Such an activity on innate immune cells triggers a synovial fluid Th17 response. Here we report the crystal structure of NapA, determined at 2.6Å resolution, which shows that the quaternary structure of the protein is that of a dodecamer with 23 symmetry, typical of the proteins of the family. We also demonstrate that the N- and C-terminal tails, which are flexible and not visible in the crystal, are not relevant for its pro-Th17 activity. Based on the crystal structure and on the comparison with the structure of the orthologous protein from Helicobacter pylori, HP-NAP, we hypothesize that the charge distributions on the two proteins' surfaces are responsible for the interaction with TLR2 and for the different behaviors in modulating the immune response.
Codolo
Gaia
G
Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padua, Italy.
Papinutto
Elena
E
Polenghi
Alessandra
A
D'Elios
Mario Milco
MM
Zanotti
Giuseppe
G
de Bernard
Marina
M
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009154:Mutation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D019743:Chemokines, CXC; D016207:Cytokines; D007155:Immunologic Factors; C534091:NapA protein, Borrelia burgdorferi; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2