title: Chemokine arrest signals to leukocyte integrins trigger bi-directional-occupancy of individual heterodimers by extracellular and cytoplasmic ligands.
abstract: Integrin heterodimers acquire high affinity to endothelial ligands by extensive conformational changes in both their alpha and beta subunits. These heterodimers are maintained in an inactive state by inter-subunit constraints. Changes in the cytoplasmic interface of the integrin heterodimer (referred to as inside-out integrin activation) can only partially remove these constraints. Full integrin activation is achieved when both inter-subunit constraints and proper rearrangements of the integrin headpiece by its extracellular ligand (outside-in activation) are temporally coupled. A universal regulator of these integrin rearrangements is talin1, a key integrin-actin adaptor that regulates integrin conformation and anchors ligand-occupied integrins to the cortical cytoskeleton. The arrest of rolling leukocytes at target vascular sites depends on rapid activation of their alpha4 and beta2 integrins at endothelial contacts by chemokines displayed on the endothelial surface. These chemotactic cytokines can signal within milliseconds through specialized Gi-protein coupled receptors (GPCRs) and Gi-triggered GTPases on the responding leukocytes. Some chemokine signals can alter integrin conformation by releasing constraints on integrin extension, while other chemokines activate integrins to undergo conformational activation mainly after ligand binding. Both of these modalities involve talin1 activation. In this opinion article, I propose that distinct chemokine signals induce variable strengths of associations between talin1 and different target integrins. Weak interactions of the integrin cytoplasmic tail with talin1 (the cytoplasmic integrin ligand) dissociate unless the extracellular ligand can simultaneously occupy the integrin headpiece and transmit, within milliseconds, proper allosteric changes across the integrin heterodimer back to the tail-talin1 complex. The fate of this bi-directional occupancy of integrins by both their extracellular and intracellular ligands is likely to benefit from immobilization of both ligands to cortical cytoskeletal elements. To properly anchor talin1 onto the integrin tail, a second integrin partner, Kindlin-3 may be also required, although an evidence that both partners can simultaneously bind the same integrin heterodimer is still missing. Once linked to the cortical actin cytoskeleton, the multi-occupied integrin complex can load weak forces, which deliver additional allosteric changes to the integrin headpiece resulting in further bond strengthening. Surface immobilized chemokines are superior to their soluble counterparts in driving this bi-directional occupancy process, presumably due to their ability to facilitate local co-occupancy of individual integrin heterodimers with talin1, Kindlin-3 and surface-bound extracellular ligands.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel. ronen.alon@weizmann.ac.il
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
mesh_terms: D000818:Animals; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism*; D008954:Models, Biological; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D018925:Chemokines; D016023:Integrins