Title:
"Binding cooperativity of membrane adhesion receptors – from statistical mechanics to immune cell signaling”

November 12, A-1-08. Speaker: dr hab. Bartosz Różycki (Instytut Fizyki Polskiej Akademii Nauk w Warszawie).

 

Adhesion of membranes that enclose cells and cellular organelles is essential for immune responses, tissue formation, and signaling. These adhesion processes result from the binding of receptor and ligand proteins that are anchored in apposing membranes. A central question is how to characterize the binding affinity of these membrane-anchored proteins. For soluble molecules, the binding affinity is typically quantified by the binding equilibrium constant K in the linear relation [RL] = K[R][L] between the volume concentration [RL] of molecular complexes and the volume concentrations [R] and [L] of unbound molecules. For membrane-anchored molecules, it is often assumed by analogy that the area concentration of receptor-ligand complexes [RL] is proportional to the product [R][L] of the area concentrations for the unbound receptor and ligand molecules. Using the Helfrich theory and equilibrium statistical mechanics, we have shown (i) that this analogy is only valid for planar membranes immobilized on rigid surfaces, (ii) that membrane shape fluctuations on nanoscales lead to cooperative binding of receptors and ligands and (iii) that, in the limit of weak adhesion, the area concentration ratio [R][L]/[RL] is proportional to the roughness of thermally fluctuating membranes [1]. Our theoretical predictions of membrane-mediated binding cooperativity have been quantitatively confirmed in molecular dynamics simulations [2] and, very recently, in fluorescence experiments on vesicles generated from plasma membranes that adhere via the SIRPα-CD47 protein complexes [3]. The experiments show that slight acidity (pH=6) stiffens membranes, diminishes cooperative interactions, and also reduces 'self' signaling of cancer cells in phagocytosis. Our results demonstrate that sensitivity of cell-cell interactions to microenvironmental factors – such as acidity of tumors and other diseased or inflamed sites – can arise from collective, cooperative properties of cell membranes.

References:
[1] H. Krobath, B. Rozycki, R. Lipowsky, T.R. Weikl. Binding cooperativity of membrane adhesion receptors. Soft Matter 17, 3354-3361 (2009).
[2] J. Hu, R. Lipowsky, T.R. Weikl. Binding constants of membrane-anchored receptors and ligands depend strongly on the nanoscale roughness of membranes. PNAS 110, 15283-15288 (2013).
[3] J. Steinkuehler, B. Rozycki, C. Alvey, R. Lipowsky, T.R. Weikl, R. Dimova, D.E. Discher. Membrane fluctuations and acidosis regulate cooperative binding of 'marker of self' protein CD47 with the macrophage checkpoint receptor SIRPα. J. Cell Sci. 132, 216770 (2019).

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