MD-2 and Der p 2 - a tale of two cousins or distant relatives?
MD-2, an LPS-binding protein is essential for the recognition of LPS by TLR4. MD-2 belongs to the ML superfamily of lipid-binding proteins. The tertiary structure of mite allergen protein Der p 2 was identified as having the protein fold most compatible with the sequence of MD-2. Comparison of MD-2 and Der p 2 reveals that they have many common biochemical characteristics: they are both rich in beta-structure and they are both very stable proteins as they both unfold only above 90 degrees C. In Der p 2, six cysteine residues form three disulfide bridges. We determined one free cysteine residue per recombinant biologically active MD-2 molecule, supporting similar disulfide topology with three disulfides bridges as in Der p 2. MD-2 binds LPS with high affinity; however, only weak binding of LPS was detected with Der p 2. Comparison of electrostatic potentials of the structural model of MD-2 and Der p 2 indicates a region of high positive potential on MD-2 and its absence in Der p 2, which may be the reason for its weak binding of LPS. We suggest that Der p 2 and its homologues probably do not have a role in response to Gram-negative bacteria in insects and that MD-2 family members with their specific role in innate immunity probably evolved from an ML ancestor only in higher vertebrates.
Keber
Mateja Mancek
MM
Laboratory of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia.
Gradisar
Helena
H
Jerala
Roman
R
D000818:Animals; D039741:Antigens, Dermatophagoides / Q000737:chemistry* / Q000276:immunology*; D000954:Antigens, Surface / Q000737:chemistry* / Q000276:immunology*; D060829:Arthropod Proteins; D005075:Biological Evolution; D002352:Carrier Proteins / Q000737:chemistry* / Q000276:immunology*; D004926:Escherichia coli; D006090:Gram-Negative Bacteria / Q000502:physiology; D007113:Immunity, Innate; D007313:Insecta / Q000276:immunology; D051218:Lymphocyte Antigen 96; D017434:Protein Structure, Tertiary; D017385:Sequence Homology; D055672:Static Electricity; D014714:Vertebrates
D039741:Antigens, Dermatophagoides; D000954:Antigens, Surface; D060829:Arthropod Proteins; D002352:Carrier Proteins; C451163:Dermatophagoides pteronyssinus antigen p 2; D051218:Lymphocyte Antigen 96