ALTERED INTERACTION OF CIS-DICHLORODIAMMINEPLATINUM(II)-MODIFIED ALPHA(2)-MACROOGLOBULIN (ALPHA(2)M) WITH THE LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN ALPHA(2)M RECEPTOR BUT NOT THE ALPHA(2)M SIGNALINGRECEPTOR - EVIDENCE FOR INTERFERENCE WITH RECEPTOR DISSOCIATION AND RECYCLING/

Receptor-recognized forms of alpha-macroglobulin (alpha(2)M) bind to two macrophage receptors: an endocytic receptor, the low density lipop rotein receptor-related protein/alpha(2)M receptor (LRP/alpha(2)MR), a nd a G protein-coupled receptor, the alpha(2)M Signaling receptor (alp ha(2)MSR). Binding of alpha(2)M to LRP/alpha(2)MR but not alpha(2)MSR is inhibited by receptor-associated protein, We now present binding c haracteristics of alpha(2)MSR (K-d similar to 50 pM; 1,530 sites/cell) using Scatchard analysis. We also demonstrate that chemical modificat ion of alpha(2)M with cis-dichlorodiammineplatinum (cis-DDP) does not significantly alter binding to either receptor or signaling character istics as compared with unmodified alpha 2M. However, internalization by LRP/alpha(2)MR is greatly affected, Cis-DDP-modified alpha(2)M (c is-DDP-alpha(2)M) and alpha(2)M* show comparable internalization duri ng a single round of endocytosis; however, cis-DDP modification of alp ha(2)M results in a greater than or equal to 82% reduction in interna lization involving receptor recycling and multiple rounds of endocytos is. Results from PH 5.0 dissociation and receptor recycling experiment s suggest that the mechanism of decreased internalization of cis-DDP-a lpha(2)M involves poor dissociation from the receptor in endosomes an d a decrease in available surface receptors over the time of exposure to the ligand.