Membrane-Mediated Cooperative Interactions of CD47 and SIRP

The specific binding of the ubiquitous 'marker of self' protein CD47 to the SIRP alpha protein anchored in the macrophage plasma membrane results in the inhibition of the engulfment of 'self' cells by macrophages and thus constitutes a key checkpoint of our innate immune system. Consequently, the CD47-SIRP alpha protein complex has been recognized as a potential therapeutic target in cancer and inflammation. Here, we introduce a lattice-based mesoscale model for the biomimetic system studied recently in fluorescence microscopy experiments where GFP-tagged CD47 proteins on giant plasma membrane vesicles bind to SIRP alpha proteins immobilized on a surface. Computer simulations of the lattice-based mesoscale model allow us to study the biomimetic system on multiple length scales, ranging from single nanometers to several micrometers and simultaneously keep track of single CD47-SIRP alpha binding and unbinding events. Our simulations not only reproduce data from the fluorescence microscopy experiments but also are consistent with results of several other experiments, which validates our numerical approach. In addition, our simulations yield quantitative predictions on the magnitude and range of effective, membrane-mediated attraction between CD47-SIRP alpha complexes. Such detailed information on CD47-SIRP alpha interactions cannot be obtained currently from experiments alone. Our simulation results thus extend the present understanding of cooperative effects in CD47-SIRP alpha interactions and may have an influence on the advancement of new cancer treatments.