Energy landscape differences among integrins establish the framework for understanding activation

Li, Jing; Springer, T.A.

doi:10.1083/jcb.201701169

Cited by 54 publications

(100 citation statements)

References 59 publications

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“…Surface molecules are often linked to cytoskeleton, sitting on the lipid bilayer of the cell membrane, or associated with intracellular signaling molecules. It has been found that the molecular length, dimension and orientation, cell surface roughness, membrane nanostructure, cytoskeleton polymerization, lipid composition, and molecular/cellular signaling can profoundly impact 2D receptor-ligand binding kinetics [11,19,[29][30][31][60][61][62][63][64][65][66]. Several 2D techniques have been used to measure the molecular interactions at live T-cell membranes with pMHCs presented by surrogate APCs or supported planar lipid bilayers.…”

Section: Two-dimensional Tcr Binding Kineticsmentioning

confidence: 99%

T-Cell Mechanobiology: Force Sensation, Potentiation, and Translation

2019

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A T cell is a sensitive self-referential mechanical sensor. Mechanical forces influence the recognition, activation, differentiation, and function throughout the lifetime of a T cell. T cells constantly perceive and respond to physical stimuli through their surface receptors, cytoskeleton, and subcellular structures. Surface receptors receive physical cues in the form of forces generated through receptor-ligand binding events, which are dynamically regulated by contact tension, shear stress, and substrate rigidity. The resulting mechanotransduction not only influences T-cell recognition and signaling but also possibly modulates cell metabolism and gene expression. Moreover, forces also dynamically regulate the deformation, organization, and translocation of cytoskeleton and subcellular structures, leading to changes in T-cell mobility, migration, and infiltration. However, the roles and mechanisms of how mechanical forces modulate T-cell recognition, signaling, metabolism, and gene expression, are largely unknown and underappreciated. Here, we review recent technological and scientific advances in T-cell mechanobiology, discuss possible roles and mechanisms of T-cell mechanotransduction, and propose new research directions of this emerging field in health and disease.

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Section: Two-dimensional Tcr Binding Kineticsmentioning

confidence: 99%

T-Cell Mechanobiology: Force Sensation, Potentiation, and Translation

2019

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“…Integrins α 4 β 1 , α 5 β 1 , and α V β 6 all appear to have bent-closed, extended-closed, and extended-open conformations. This conclusion is directly demonstrated for α 5 β 1 and α V β 6 by EM (10,11) and may be inferred for α 4 β 1 by the effects of Fabs that stabilize the closed, open, and extended states on affinity of soluble α 4 β 1 fragments for ligands and α 4 β 1 -dependent cell adhesion to specific ligand (6). We therefore interpret the increase in α Values are mean ± SD for one measurement each with Fn3 7-10 , Fn3 8-10 , and Fn3 9-10 , with the exception of the headpiece in Mg 2+ , for which Fn3 7-10 and Fn3 9-10 results could not be fit, and the fit ± fitting error is shown for Fn3 8-10 .…”

Section: Discussionmentioning

confidence: 63%

“…We place our results in the context of recent thermodynamic studies on β 1 integrins that have shown how ligand-binding affinities are regulated by integrin conformational change. Studies on α 4 β 1 and α 5 β 1 showed that affinities of their open conformations were 5,000-fold (α 5 β 1 ) and 700-fold (α 4 β 1 ) higher than their closed conformations and that these affinities were intrinsic, that is, independent of whether the conformation was on the cell surface or in a particular integrin fragment (5,6,10). Differences in affinities among cell-surface integrins and different integrin fragments were caused by differences in relative free energies of conformational states (and their populations) within ensembles in each type of integrin preparations.…”

Section: Discussionmentioning

confidence: 99%

“…1C) (3). The extendedopen integrin conformation of α L β 2 , α 4 β 1 , and α 5 β 1 integrins has ∼1,000-fold higher affinity for ligand than the bent-closed and extended-closed conformations (4)(5)(6).…”

mentioning

confidence: 98%

“…Therefore, it was proposed that the hybrid domain interface stabilizes the βI domain in the closed conformation (3); however, this hypothesis has not yet been tested. This is an important question, because many studies have demonstrated that headpiece opening is the key step in integrin affinity maturation (3)(4)(5)(6)9).…”

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confidence: 99%

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High integrin α _V β ₆ affinity reached by hybrid domain deletion slows ligand-binding on-rate

Dong

Zhao

Lin³

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The role of the hybrid domain in integrin affinity regulation is unknown, as is whether the kinetics of ligand binding is modulated by integrin affinity state. Here, we compare cell surface and soluble integrin αβ truncation mutants for ligand-binding affinity, kinetics, and thermodynamics. Removal of the integrin transmembrane/cytoplasmic domains or lower legs has little effect on αβ affinity, in contrast to β integrins. In integrin opening, rearrangement at the interface between the βI and hybrid domains is linked to remodeling at the ligand-binding site at the opposite end of the βI domain, which greatly increases in affinity in the open conformation. The larger size of the βI-hybrid interface in the closed state suggests that the hybrid domain stabilizes closing. In agreement, deletion of the hybrid domain raised affinity by 50-fold. Surface plasmon resonance and isothermal titration calorimetry gave similar results and the latter revealed tradeoffs between enthalpy and entropy not apparent from affinity. At extremely high affinity reached in Mn with hybrid domain truncation, αβ on-rate for both pro-TGF-β1 and fibronectin declined. The results suggest that the open conformation of αβ has lower on-rate than the closed conformation, correlate with constriction of the ligand-binding pocket in open αβ structures, and suggest that the extended-closed conformation is kinetically selected for ligand binding. Subsequent transition to the extended-open conformation is stabilized by its much higher affinity for ligand and would also be stabilized by force exerted across ligand-bound integrins by the actin cytoskeleton.

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A Multifunctional Nanostructured Hydrogel as a Platform for Deciphering Niche Interactions of Hematopoietic Stem and Progenitor Cells

Ludwig‐Husemann,

Schertl,

Shrivastava

et al. 2024

Adv Healthcare Materials

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For over half a century, hematopoietic stem cells (HSCs) have been used for transplantation therapy to treat severe hematologic diseases. Successful outcomes depend on collecting sufficient donor HSCs as well as ensuring efficient engraftment. These processes are influenced by dynamic interactions of HSCs with the bone marrow niche, which can be revealed by artificial niche models. Here, a multifunctional nanostructured hydrogel is presented as a 2D platform to investigate how the interdependencies of cytokine binding and nanopatterned adhesive ligands influence the behavior of human hematopoietic stem and progenitor cells (HSPCs). The results indicate that the degree of HSPC polarization and motility, observed when cultured on gels presenting the chemokine SDF‐1α and a nanoscale‐defined density of a cellular (IDSP) or extracellular matrix (LDV) α4β1 integrin binding motif, are differently influenced on hydrogels functionalized with the different ligand types. Further, SDF‐1α promotes cell polarization but not motility. Strikingly, the degree of differentiation correlates negatively with the nanoparticle spacing, which determines ligand density, but only for the cellular‐derived IDSP motif. This mechanism potentially offers a means of predictably regulating early HSC fate decisions. Consequently, the innovative multifunctional hydrogel holds promise for deciphering dynamic HSPC‐niche interactions and refining transplantation therapy protocols.

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Energy landscape differences among integrins establish the framework for understanding activation

Cited by 54 publications

References 59 publications

T-Cell Mechanobiology: Force Sensation, Potentiation, and Translation

T-Cell Mechanobiology: Force Sensation, Potentiation, and Translation

High integrin α _V β ₆ affinity reached by hybrid domain deletion slows ligand-binding on-rate

A Multifunctional Nanostructured Hydrogel as a Platform for Deciphering Niche Interactions of Hematopoietic Stem and Progenitor Cells

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Energy landscape differences among integrins establish the framework for understanding activation

Cited by 54 publications

References 59 publications

T-Cell Mechanobiology: Force Sensation, Potentiation, and Translation

T-Cell Mechanobiology: Force Sensation, Potentiation, and Translation

High integrin α V β 6 affinity reached by hybrid domain deletion slows ligand-binding on-rate

A Multifunctional Nanostructured Hydrogel as a Platform for Deciphering Niche Interactions of Hematopoietic Stem and Progenitor Cells

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Product

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High integrin α _V β ₆ affinity reached by hybrid domain deletion slows ligand-binding on-rate