title: Mechanical modulation of receptor-ligand interactions at cell-cell interfaces.
abstract: Cell surface receptors have been extensively studied because they initiate and regulate signal transduction cascades leading to a variety of functional cellular outcomes. An important class of immune receptors (e.g., T-cell antigen receptors) whose ligands are anchored to the surfaces of other cells remain poorly understood. The mechanism by which ligand binding initiates receptor phosphorylation, a process termed "receptor triggering", remains controversial. Recently, direct measurements of the (two-dimensional) receptor-ligand complex lifetimes at cell-cell interface were found to be smaller than (three-dimensional) lifetimes in solution but the underlying mechanism is unknown. At the cell-cell interface, the receptor-ligand complex spans a short intermembrane distance (15 nm) compared to long surface molecules (LSMs) whose ectodomains span >40 nm and these LSMs include phosphatases (e.g., CD45) that dephosphorylate the receptor. It has been proposed that size-based segregation of LSMs from a receptor-ligand complex is a mechanism of receptor triggering but it is unclear whether the mechanochemistry supports such small-scale segregation. Here we present a nanometer-scale mathematical model that couples membrane elasticity with the compressional stiffness and lateral mobility of LSMs. We find robust supradiffusive segregation of LSMs from a single receptor-ligand complex. The model predicts that LSM redistribution will result in a time-dependent tension on the complex leading to a decreased two-dimensional lifetime. Interestingly, the model predicts a nonlinear relationship between the three- and two-dimensional lifetimes, which can enhance the ability of receptors to discriminate between similar ligands.
authors.affiliation: Department of Mathematics, University of California, Davis, California, USA.
authors.forename: Jun F
authors.initials: JF
authors.lastname: Allard
authors.forename: Omer
authors.initials: O
authors.lastname: Dushek
authors.forename: Daniel
authors.initials: D
authors.lastname: Coombs
authors.forename: P A
authors.initials: PA
authors.lastname: van der Merwe
mesh_terms: D001696:Biomechanical Phenomena / Q000502:physiology; D002450:Cell Communication; D008024:Ligands; D008954:Models, Biological; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013997:Time Factors
chemical_list: D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface