Ligand-independent receptor clustering modulates transmembrane signaling: a new paradigm

Receptor clustering in living cells is being increasingly recognized not only as an essential facet of cell signaling but also as a physical modulator of physiological responses. Liquid–liquid phase separation as the main mechanism for cluster formation indicates that, in addition to ligand binding, proximity to molecules, critical concentration thresholds, physical forces, and other aspects may direct cell signaling. Novel approaches to modulate ligand–receptor interactions 'on-demand' show that receptor clustering can trigger diverse cellular outcomes in the absence of ligands. Studies of ligand-independent clustering may stimulate the future development of unique therapeutics that target and manipulate receptors and their signaling pathways with high specificity and spatiotemporal control. Cell-surface receptors mediate communication between cells and their environment. Lateral membrane organization and dynamic receptor cluster formation are fundamental in signal transduction and cell signaling. However, it is not yet fully understood how receptor clustering modulates a wide variety of physiologically relevant processes. Recent growing evidence indicates that biological responses triggered by membrane receptors can be modulated even in the absence of the natural receptor ligand. We review the most recent findings on how ligand-independent receptor clustering can regulate transmembrane signaling. We discuss the latest technologies to control receptor assembly, such as DNA nanotechnology, optogenetics, and optochemistry, focusing on the biological relevance and unraveling of ligand-independent signaling. Cell-surface receptors mediate communication between cells and their environment. Lateral membrane organization and dynamic receptor cluster formation are fundamental in signal transduction and cell signaling. However, it is not yet fully understood how receptor clustering modulates a wide variety of physiologically relevant processes. Recent growing evidence indicates that biological responses triggered by membrane receptors can be modulated even in the absence of the natural receptor ligand. We review the most recent findings on how ligand-independent receptor clustering can regulate transmembrane signaling. We discuss the latest technologies to control receptor assembly, such as DNA nanotechnology, optogenetics, and optochemistry, focusing on the biological relevance and unraveling of ligand-independent signaling. an agonist is a ligand that interacts with a specific membrane receptor and elicits a positive response. Agonist bias refers to the propensity of an agonist to direct receptor signaling through one pathway relative to another. For GPCRs, signaling bias may refer to preferential activation of β-arrestin-dependent signaling compared to G protein-dependent signaling. An inverse agonist is a ligand that inhibits constitutive receptor activity. An antagonist is a ligand or drug that binds to the receptor and inhibits a biological response. liquid-like membraneless compartments that are enriched in proteins, RNA, and other biomolecules that perform distinct functions inside cells. the region between plasma membranes of two cells in contact. These compartments display a unique subcellular environment defined by specific molecules and biophysical properties, which differ from the rest of the plasma membrane. receptor activation and signaling in the absence of ligand. Constitutive activity has been well characterized for GPCRs where receptors and G proteins exist in an equilibrium between active and inactive state. However, receptor clustering, phase separation, and mechanical stimuli can also influence this activation. DNA is a chemical material with highly designable, predictable, and controllable properties and can be used as a building block for the construction of diverse nanostructures. higher-order assemblies with a size of hundreds of nanometers, rather than dimers or trimers, which may be formed during receptor signaling. the stable interface between a T cell and an antigen-presenting cell (APC). IS assembly is triggered when an APC presents a specific peptide antigen in association to a major histocompatibility complex (MHC) molecule (pMHC:TCR). IS formation involves a spatiotemporal redistribution of T cell receptors (TCRs), costimulatory receptors, and integrins, leading to a highly dynamic TCR signaling hub. a compartmentalization mechanism in which multivalent macromolecular interactions drive the transition of proteins or nucleic acids into a concentrated phase. physical signals detected through mechanoreceptors. The mechanical stimulus is usually applied to membrane receptors on cells in direct physical contact with the extracellular matrix (ECM) or on adjacent cells through ligand binding. receptor assemblies of several hundreds of nanometers. the process by which molecules spontaneously associate through noncovalent interactions into stable, well-defined structures. the optical control of biomolecules with high spatiotemporal resolution via optochemical tools such as engineered proteins, photoactive small molecules, peptides, or nucleic acids. a set of methods to precisely control the biological functions of cells, tissues, or organs with high spatiotemporal resolution by using genetically encoded light-sensitive proteins. non-stoichiometric assemblies driven by combinatorial multivalent interactions that are heterogeneous in size and state. an assembly of receptors and their effectors at the plasma membrane. the nanoscale shape and spatial arrangement of elements which directly interact with the plasma membrane of a living cell. a novel interdisciplinary research area following engineering principles to redesign and construct biological systems for useful purposes. top-down approaches equip existing cells with new functionalities, whereas bottom-up approaches use biological building blocks to construct modules that can be used to recreate cell functions in vitro.