Reversible self-association of a human myeloma protein. Thermodynamics and relevance to viscosity effects and solubility.

Monoclonal IgG paraproteins associated with multiple myeloma, Felty's syndrome, and idiopathic cryoglobulinemia frequently produce disease due to a tendency to self-associate in vivo. The insolubility and viscosity effects of these proteins are of specific interest as molecular disease mechanisms. In sedimentation equilibrium studies at 21 degrees C an IgG1-lambda myeloma protein (IgG-MIT) associated with the hyperviscosity syndrome is shown to undergo a reversible polymerization reaction. On the basis of the theory and data-fitting methods of Adams and co-workers [Tang, L. H., Powell, D. R., Escott, B. M., & Adams, E. T., Jr. (1977) Biophys. Chem. 7, 121-139], the data are consistent with a nonideal cooperative indefinite (SEK type III) model self-association in which one equilibrium constant (K12 = 6.3 X 10(3) L/m) governs dimerization while another (K = 1.7 X 10(4) L/m) governs all subsequent additions of monomer to the polymer. Temperature effects on K12 and K between 11 and 30 degrees C suggest negative van't Hoff enthalpies for all association steps and a positive entropy change [delta S degree = 2.5 cal/(mol-deg)] for steps beyond the dimer. An increase in ionic strength from I = 0.03 to I = 0.18 promotes the polymerization of IgG-MIT through a marked increase in K while paradoxically enhancing bulk solubility. These results suggest that this self-association proceeds through a combination of weak nonionic and hydrophobic interactions. The enhancement of both polymerization and solubility by increased ionic strength suggests that the hyperviscosity induced by IgG-MIT results from its ability to form large, highly soluble polymers in serum.(ABSTRACT TRUNCATED AT 250 WORDS)