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Energy landscape differences among integrins establish the framework for understanding activation.

ABSTRACT: Why do integrins differ in basal activity, and how does affinity for soluble ligand correlate with cellular adhesiveness? We show that basal conformational equilibrium set points for integrin α₄β₁ are cell type specific and differ from integrin α₅β₁ when the two integrins are coexpressed on the same cell. Although α₄β₁ is easier to activate, its high-affinity state binds vascular cell adhesion molecule and fibronectin 100- to 1,000-fold more weakly than α₅β₁ binds fibronectin. Furthermore, the difference in affinity between the high- and low-affinity states is more compressed in α₄β₁ (600- to 800-fold) than in α₅β₁ (4,000- to 6,000-fold). α₄β₁ basal conformational equilibria differ among three cell types, define affinity for soluble ligand and readiness for priming, and may reflect differences in interactions with intracellular adaptors but do not predict cellular adhesiveness for immobilized ligand. The measurements here provide a necessary framework for understanding integrin activation in intact cells, including activation of integrin adhesiveness by application of tensile force by the cytoskeleton, across ligand-integrin-adaptor complexes.

SUBMITTER: Li J

PROVIDER: S-EPMC5748972 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Energy landscape differences among integrins establish the framework for understanding activation.

Li Jing J Springer Timothy A TA

The Journal of cell biology 20171109 1

Why do integrins differ in basal activity, and how does affinity for soluble ligand correlate with cellular adhesiveness? We show that basal conformational equilibrium set points for integrin α4β1 are cell type specific and differ from integrin α5β1 when the two integrins are coexpressed on the same cell. Although α4β1 is easier to activate, its high-affinity state binds vascular cell adhesion molecule and fibronectin 100- to 1,00 ...[more]

PMID: 29122968

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Project description:Liquid-liquid phase separation (LLPS) inside the cell often results in biological condensates that can critically impact cell homeostasis. Such phase separation events occur in multiple parts of cells, including the cell membranes, where the so-called "lipid raft" hypothesis posits the formation of ordered domains floating in a sea of disordered lipids. The resulting lipid domains often have functional roles. However, the thermodynamics of lipid phase separation and their resulting mechanistic effects on cell function and dysfunction are poorly understood. Understanding such complex phenomena in cell membranes, with their diverse lipid compositions, is exceptionally difficult. For this reasons, simple model systems that can recapitulate similar behavior are widely used to study this phenomenon. Despite these simplifications, the timescale and and length scales of domain formation pose a challenge for molecular dynamics (MD) simulations. Thus, most MD studies focus on spontaneous lipid phase separation - essentially measuring the sign (but not the amplitude) of the free energy change upon separation - rather than directly interrogating the thermodynamics. Here, we propose a proof-of-concept pipeline that can directly measure this free energy by combining coarse-grained MD with enhanced sampling protocols using a novel collective variable. This approach will be a useful tool to help connect the thermodynamics of phase separation with the mechanistic insights already available from molecular dynamics simulations.SignificanceStandard molecular dynamics simulations can determine the sign the free energy change upon phase separation, but not the amplitude. We present a new method to determine the phase separation free energy for lipid membranes, based on a enhanced sampling using the weighted ensemble method combined with a novel collective variable, validated using coarse-grained simulations applied to several simple systems. The new method will be valuable as a way to develop models that connect molecular-level structural features to the thermodynamics of phase separation.

Dataset Information

Energy landscape differences among integrins establish the framework for understanding activation.

Publications

Energy landscape differences among integrins establish the framework for understanding activation.

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