Recognition of IgG-derived peptides by a human IgM with an unusual combining site.
A monoclonal immunoglobulin (Ig)M cryoglobulin (Mez) with interesting binding behaviour was isolated from a Waldenström's macroglobulinemia (WM) patient. It demonstrated very strong binding to peptides derived from the sequences of human IgG. However, when tested for binding to intact IgG, this antibody (Ab) did not show any rheumatoid factor (RF) activity. We propose several nonexclusive structural interpretations of the Mez-binding propensities, based on the orientations and solvent accessibilities of ligand residues and the nature of the Ab-binding site. To further characterize the structural features of Mez-peptide binding, IgG-derived octapeptides were docked into the Mez fragment variable (Fv)-binding site, revealing additional reasons for Mez-binding selectivity based on the interactions of the docked peptides with the Mez Fv. The problem was also approached from an immunological perspective. Comparisons of Mez variable region of the light chain (VL)/variable region of the heavy chain (VH) sequences with those of human germlines and known IgM RFs allowed us to provide a possible outline tracing the structural and functional origins of the Mez IgM. Coupled with examinations of interactions in docked complexes, this analysis led us to propose that the potential for RF activity, demonstrated through Mez binding to IgG-derived peptides, was owing to the inherent sequence and structure of the Mez IgM, rather than to somatic mutations. Thus, Mez IgM may occupy an intermediate niche between IgMs with and without RF activity.
Yuriev
E
E
Crystallography Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Ramsland
P A
PA
Edmundson
A B
AB
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001666:Binding Sites, Antibody; D003450:Cryoglobulins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007075:Immunoglobulin M / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011485:Protein Binding; D011487:Protein Conformation; D012217:Rheumatoid Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D003450:Cryoglobulins; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D010446:Peptide Fragments; C055966:immunoglobulin Fv; D012217:Rheumatoid Factor