title: Cargo binding promotes KDEL receptor clustering at the mammalian cell surface.
abstract: Transmembrane receptor clustering is a ubiquitous phenomenon in pro- and eukaryotic cells to physically sense receptor/ligand interactions and subsequently translate an exogenous signal into a cellular response. Despite that receptor cluster formation has been described for a wide variety of receptors, ranging from chemotactic receptors in bacteria to growth factor and neurotransmitter receptors in mammalian cells, a mechanistic understanding of the underlying molecular processes is still puzzling. In an attempt to fill this gap we followed a combined experimental and theoretical approach by dissecting and modulating cargo binding, internalization and cellular response mediated by KDEL receptors (KDELRs) at the mammalian cell surface after interaction with a model cargo/ligand. Using a fluorescent variant of ricin toxin A chain as KDELR-ligand (eGFP-RTA(H/KDEL)), we demonstrate that cargo binding induces dose-dependent receptor cluster formation at and subsequent internalization from the membrane which is associated and counteracted by anterograde and microtubule-assisted receptor transport to preferred docking sites at the plasma membrane. By means of analytical arguments and extensive numerical simulations we show that cargo-synchronized receptor transport from and to the membrane is causative for KDELR/cargo cluster formation at the mammalian cell surface.
authors.affiliation: Molecular and Cell Biology, Department of Biosciences and Center of Human and Molecular Biology (ZHMB), Saarland University, D-66041 Saarbrücken, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Becker
authors.affiliation: Department of Theoretical Physics, Saarland University, D-66041 Saarbrücken, Germany.
authors.forename: M Reza
authors.initials: MR
authors.lastname: Shaebani
authors.affiliation: Molecular and Cell Biology, Department of Biosciences and Center of Human and Molecular Biology (ZHMB), Saarland University, D-66041 Saarbrücken, Germany.
authors.forename: Domenik
authors.initials: D
authors.lastname: Rammo
authors.affiliation: Molecular and Cell Biology, Department of Biosciences and Center of Human and Molecular Biology (ZHMB), Saarland University, D-66041 Saarbrücken, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bubel
authors.affiliation: Department of Theoretical Physics, Saarland University, D-66041 Saarbrücken, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Santen
authors.affiliation: Molecular and Cell Biology, Department of Biosciences and Center of Human and Molecular Biology (ZHMB), Saarland University, D-66041 Saarbrücken, Germany.
authors.forename: Manfred J
authors.initials: MJ
authors.lastname: Schmitt
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding; D021381:Protein Transport; D018000:Receptors, Peptide / Q000737:chemistry* / Q000378:metabolism*; D012276:Ricin / Q000378:metabolism*
chemical_list: C064459:KDEL receptor; D018000:Receptors, Peptide; D012276:Ricin