Conformational equilibria and intrinsic affinities define integrin activation

Li, Jing; Su, Yang; Xia, Wei; Yan, Qin; Humphries, Martin J.; Vestweber, Dietmar; Cabañas, Carlos; Lu, Chafen; Springer, T.A.

doi:10.15252/embj.201695803

The EMBO Journal

2017

DOI: 10.15252/embj.201695803

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Conformational equilibria and intrinsic affinities define integrin activation

Jing Li

Yang Su

Wei Xia

et al.

Abstract: We show that the three conformational states of integrin α5β1 have discrete free energies and define activation by measuring intrinsic affinities for ligand of each state and the equilibria linking them. The 5,000‐fold higher affinity of the extended‐open state than the bent‐closed and extended‐closed states demonstrates profound regulation of affinity. Free energy requirements for activation are defined with protein fragments and intact α5β1. On the surface of K562 cells, α5β1 is 99.8% bent‐closed. Stabilizat… Show more

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Cited by 115 publications

(226 citation statements)

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“…S9); i.e., the Hill slope is fixed at 1. All plots fit this model well, except for Mg the conformational equilibrium toward the open headpiece conformation and raises its intrinsic affinity (12). An increase in intrinsic affinity of the closed conformation must account for the two-to threefold higher affinity in Mn 2+ compared with Mg 2+ of α V β 8 for pro-TGF-β1 found here because EM showed that α V β 8 had a closed conformation when bound to pro-TGF-β1 in both Mn 2+ and Mg 2+ .…”

mentioning

confidence: 67%

“…The 100-nM affinity of α V β 8 for pro-TGF-β1 is indeed ∼100-fold higher than the affinity for biological ligand of the closed conformations of α 5 β 1 (12). However, the fairest comparison is between α V β 8 and α V β 6 binding to the same ligand, pro-TGF-β1.…”

mentioning

confidence: 94%

“…1). The extended-open integrin conformation has much higher ligand binding affinity than the bent-closed or extended-closed conformations (11,12). Previously, it has been reported that integrin α V β 8 is constitutively extended and does not undergo headpiece opening in the presence of an RGD peptide (13).…”

mentioning

confidence: 99%

“…Because other integrins exist in an ensemble of conformations, measurements of their affinities represent an average of the affinity of each conformation weighted by the population of that conformation in the ensemble. By using Fabs of the allostery conformation-specific antibodies to stabilize integrin α 5 β 1 in open, closed, and extended conformations, we have been able to measure the affinity intrinsic to each integrin conformation (12). The affinity of fibronectin for the extended-open conformation of α 5 β 1 is 1.4 nM and for the bent-closed and extended-closed conformations is ∼9,000 nM.…”

mentioning

confidence: 99%

“…Additionally, the presence of a small proportion of the open headpiece in the α V β 6 conformational ensemble in Mg 2+ is likely to account for the 30-fold higher affinity for pro-TGF-β1 in Mg 2+ of α V β 6 compared with α V β 8 . Given the ∼1,000-fold higher affinity of integrin open than closed states, a small percentage of the open conformation can make a major contribution to ensemble affinity (12).…”

mentioning

confidence: 99%

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Atypical interactions of integrin α _V β ₈ with pro-TGF-β1

Wang

Dong

Zhao

et al. 2017

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

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Integrins α V β 6 and α V β 8 are specialized for recognizing pro-TGF-β and activating its growth factor by releasing it from the latency imposed by its surrounding prodomain. The integrin α V β 8 is atypical among integrins in lacking sites in its cytoplasmic domain for binding to actin cytoskeleton adaptors. Here, we examine α V β 8 for atypical binding to pro-TGF-β1. In contrast to α V β 6 , α V β 8 has a constitutive extended-closed conformation, and binding to pro-TGF-β1 does not stabilize the open conformation of its headpiece. Although Mn 2+ potently activates other integrins and increases affinity of α V β 6 for pro-TGF-β1 25-to 55-fold, it increases α V β 8 affinity only 2-to 3-fold. This minimal effect correlates with the inability of Mn 2+ and pro-TGF-β1 to stabilize the open conformation of the α V β 8 headpiece. Moreover, α V β 8 was inhibited by high concentrations of Mn 2+ and was stimulated and inhibited at markedly different Ca 2+ concentrations than α V β 6 . These unusual characteristics are likely to be important in the still incompletely understood physiologic mechanisms that regulate α V β 8 binding to and activation of pro-TGF-β.integrins | allostery | pro-TGF-β1 I ntegrins are cell-surface adhesion molecules that mediate cellcell, cell-extracellular matrix, and cell-pathogen interactions. In mammals, 24 different integrins are formed by specific, noncovalent association of 18 α-subunits with 8 β-subunits (1-5). Almost all integrins link to the actin cytoskeleton through talin and kindlin-binding motifs in their β-subunit cytoplasmic domains and thus provide traction for cell migration. The only exceptions are integrin α V β 8 , which binds through its β 8 -subunit to differentially express in adenocarcinoma of the lung (DAL-1, also known as Band 4.1B), and integrin α 6 β 4 , which links through its β 4 -subunit to intermediate filaments (6).Here, we focus on the atypical integrin α V β 8 and compare it to integrin α V β 6 . Integrins α V β 6 and α V β 8 are specialized for binding to and activation of pro-TGF-β1 and -β3. The pro-TGF-βs are biosynthesized and stored in tissues as latent forms. The dimeric TGF-β growth factor is kept latent by noncovalent association with its dimeric prodomain, which in turn is linked noncovalently and through disulfide bonds to a "milieu molecule" that stores the latent complex in the extracellular matrix or on the cell surface for subsequent, integrin-dependent activation. Integrins bind to an RGD motif that is present in the prodomains of pro-TGF-β1 and -β3. However, integrin binding alone is not sufficient for latent TGF-β activation by α V β 6 ; force is also required. Experiments suggest that tensile force is transmitted from the cytoskeleton to the integrin, is resisted by anchorage of TGF-β1 in the extracellular matrix or on cell surfaces, and results in distortion of prodomain straitjacket elements that loosely surround the growth factor followed by release of the growth factor (7,8). In some systems, activation of TGF-β1 by α V β 8 is dependent on...

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confidence: 67%

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confidence: 94%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Atypical interactions of integrin α _V β ₈ with pro-TGF-β1

Wang

Dong

Zhao

et al. 2017

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

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Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus

Motz

Kabat

Saxena

et al. 2021

Adv Healthcare Materials

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The brain processes information by transmitting signals through highly connected and dynamic networks of neurons. Neurons use specific cellular structures, including axons, dendrites and synapses, and specific molecules, including cell adhesion molecules, ion channels and chemical receptors to form, maintain and communicate among cells in the networks. These cellular and molecular processes take place in environments rich of mechanical cues, thus offering ample opportunities for mechanical regulation of neural development and function. Recent studies have suggested the importance of mechanical cues and their potential regulatory roles in the development and maintenance of these neuronal structures. Also suggested are the importance of mechanical cues and their potential regulatory roles in the interaction and function of molecules mediating the interneuronal communications. In this review, the current understanding is integrated and promising future directions of neuromechanobiology are suggested at the cellular and molecular levels. Several neuronal processes where mechanics likely plays a role are examined and how forces affect ligand binding, conformational change, and signal induction of molecules key to these neuronal processes are indicated, especially at the synapse. The disease relevance of neuromechanobiology as well as therapies and engineering solutions to neurological disorders stemmed from this emergent field of study are also discussed.

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Static and Dynamic: Evolving Biomaterial Mechanical Properties to Control Cellular Mechanotransduction

et al. 2023

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The extracellular matrix (ECM) is a highly dynamic system that constantly offers physical, biological, and chemical signals to embraced cells. Increasing evidence suggests that mechanical signals derived from the dynamic cellular microenvironment are essential controllers of cell behaviors. Conventional cell culture biomaterials, with static mechanical properties such as chemistry, topography, and stiffness, have offered a fundamental understanding of various vital biochemical and biophysical processes, such as cell adhesion, spreading, migration, growth, and differentiation. At present, novel biomaterials that can spatiotemporally impart biophysical cues to manipulate cell fate are emerging. The dynamic properties and adaptive traits of new materials endow them with the ability to adapt to cell requirements and enhance cell functions. In this review, an introductory overview of the key players essential to mechanobiology is provided. A biophysical perspective on the state‐of‐the‐art manipulation techniques and novel materials in designing static and dynamic ECM‐mimicking biomaterials is taken. In particular, different static and dynamic mechanical cues in regulating cellular mechanosensing and functions are compared. This review to benefit the development of engineering biomechanical systems regulating cell functions is expected.

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Conformational equilibria and intrinsic affinities define integrin activation

Cited by 115 publications

References 53 publications

Atypical interactions of integrin α _V β ₈ with pro-TGF-β1

Atypical interactions of integrin α _V β ₈ with pro-TGF-β1

Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus

Static and Dynamic: Evolving Biomaterial Mechanical Properties to Control Cellular Mechanotransduction

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Conformational equilibria and intrinsic affinities define integrin activation

Cited by 115 publications

References 53 publications

Atypical interactions of integrin α V β 8 with pro-TGF-β1

Atypical interactions of integrin α V β 8 with pro-TGF-β1

Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus

Static and Dynamic: Evolving Biomaterial Mechanical Properties to Control Cellular Mechanotransduction

Contact Info

Product

Resources

About

Atypical interactions of integrin α _V β ₈ with pro-TGF-β1

Atypical interactions of integrin α _V β ₈ with pro-TGF-β1