Molecular mimicry between a monoclonal antibody and one subunit of crotoxin, a heterodimeric phospholipase A2 neurotoxin.
Crotoxin is a heterodimeric phospholipase A2 neurotoxin formed by the non-covalent association of an acidic and non-toxic subunit, CA, and a basic and weakly toxic phospholipase A2, CB. The two subunits behave in a synergistic manner. CA enhances the lethal potency of CB by increasing its selectivity of action. The mAb A-56.36, directed against the non-toxic subunit CA, was previously shown to neutralize crotoxin toxicity by dissociating the crotoxin complex. In the present report, a polypeptide sequence similarity was observed between some CDRs of mAb A-56.36 and two regions of CB (pos. 60-80 and 95-110). Phage displayed peptides corresponding to VH2 and VH3 of mAb A-56.36 and to their homologous sequences in CB bind CA to different extents. This observation shows that mAb A-56.36 interacts with a region of CA involved in its interaction with CB, therefore mimicking the binding of CB to CA. A similar approach was used to determine the regions of ammodytoxin A and of agkistrodotoxin, two phospholipase A2 neurotoxins similar to CB, which are involved in the formation of heterocomplexes with CA. The analysis of these data contributes to the determination of stretches of amino acids which could constitute the paratope of mAb A-56.36, as well as the region of association of CB with CA in crotoxin.
Choumet
V
V
Unité des Venins, Institut Pasteur, Paris, France.
Lafaye
P
P
Demangel
C
C
Bon
C
C
Mazié
J C
JC
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001435:Bacteriophages / Q000235:genetics; D003001:Cloning, Molecular; D003439:Crotoxin / Q000737:chemistry* / Q000235:genetics; D019281:Dimerization; D004797:Enzyme-Linked Immunosorbent Assay; D007135:Immunoglobulin Variable Region / Q000737:chemistry; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000737:chemistry* / Q000235:genetics; D010741:Phospholipases A / Q000737:chemistry* / Q000235:genetics; D054467:Phospholipases A2; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D000911:Antibodies, Monoclonal; D007135:Immunoglobulin Variable Region; D009498:Neurotoxins; D003439:Crotoxin; D010741:Phospholipases A; D054467:Phospholipases A2