Membrane fluctuations and acidosis regulate cooperative binding of 'marker of self' protein CD47 with the macrophage checkpoint receptor SIRPα

Journal of Cell Science
Jan SteinkühlerDennis E Discher

Abstract

Cell-cell interactions that result from membrane proteins binding weakly in trans can cause accumulations in cis that suggest cooperativity and thereby an acute sensitivity to environmental factors. The ubiquitous 'marker of self' protein CD47 binds weakly to SIRPα on macrophages, which leads to accumulation of SIRPα (also known as SHPS-1, CD172A and SIRPA) at phagocytic synapses and ultimately to inhibition of engulfment of 'self' cells - including cancer cells. We reconstituted this macrophage checkpoint with GFP-tagged CD47 on giant vesicles generated from plasma membranes and then imaged vesicles adhering to SIRPα immobilized on a surface. CD47 diffusion is impeded near the surface, and the binding-unbinding events reveal cooperative interactions as a concentration-dependent two-dimensional affinity. Membrane fluctuations out-of-plane link cooperativity to membrane flexibility with suppressed fluctuations in the vicinity of bound complexes. Slight acidity (pH 6) stiffens membranes, diminishes cooperative interactions and also reduces 'self' signaling of cancer cells in phagocytosis. Sensitivity of cell-cell interactions to microenvironmental factors - such as the acidity of tumors and other diseased or inflamed sites - can ...Continue Reading

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Citations

Oct 5, 2019·Protein Science : a Publication of the Protein Society·Dominika ChalupskaEvzen Boura
Aug 23, 2019·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Jason C AndrechakDennis E Discher
Apr 16, 2020·Physical Review. E·Hang Zang, Xinlei Li
Aug 4, 2019·International Journal of Molecular Sciences·Nidhi Singh, Wenjin Li
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Jun 28, 2020·Journal of Cell Science·Victoria JunghansPeter Jönsson
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Oct 16, 2021·Biophysical Journal·Manto ChouliaraPeter Jönsson
Dec 18, 2021·Nature Chemical Biology·Jinghua GeYongli Zhang

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