The N-terminal Flanking Region of the A1 Domain Regulates the Force-dependent Binding of von Willebrand Factor to Platelet Glycoprotein Ibα

Ju, Lining Arnold; Dong, Jing; Crúz, Miguel A.; Zhu, Cheng

doi:10.1074/jbc.m113.504001

Cited by 93 publications

(216 citation statements)

References 55 publications

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“…Using thermal fluctuation of beads coated with A1 and antibody bound to GPIbα, a zero-force off-rate of 0.2 s −1 was found (30). Transient tethers of A1-coated beads in shear flow over surfaces coated with platelets were extrapolated to zero force using the Bell model and yielded k off 0 of 3 s −1 and σ of 0.03 nm (31).…”

Section: Discussionmentioning

confidence: 99%

Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases

Kim

Hudson

Springer

2015

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

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Mutations in the ultralong vascular protein von Willebrand factor (VWF) cause the common human bleeding disorder, von Willebrand disease (VWD). The A1 domain in VWF binds to glycoprotein Ibα (GPIbα) on platelets, in a reaction triggered, in part, by alterations in flow during bleeding. Gain-of-function mutations in A1 and GPIbα in VWD suggest conformational regulation. We report that force application switches A1 and/or GPIbα to a second state with faster on-rate, providing a mechanism for activating VWF binding to platelets. Switching occurs near 10 pN, a force that also induces a state of the receptor−ligand complex with slower off-rate. Force greatly increases the effects of VWD mutations, explaining pathophysiology. Conversion of single molecule k on (s −1 ) to bulk phase k on (s −1 M −1 ) and the k on and k off values extrapolated to zero force for the low-force pathways show remarkably good agreement with bulk-phase measurements.U nderstanding how force affects receptor and ligand binding and unbinding is a long-standing effort in mechanobiology (1-5). Bond dissociation rates typically increase under mechanical stress; however, bond stability can be enhanced through specialized mechanisms induced by force, including catch bonds and switching to a slip bond with a slower off-rate (flex bonds) (6, 7). Bond formation against an applied force has recently been measured (8). Force-regulated switching to a faster on-rate has not yet been reported for any receptor−ligand bond but would have important biological implications for adhesion in environments with high forces such as the circulation.At sites of vascular injury, hydrodynamic force in the bloodstream acting on von Willebrand factor (VWF) is pivotal in regulating the binding of the VWF A1 domain to GPIbα on platelets and commencing the crosslinking of platelets by VWF to form a platelet plug (9-11). VWF circulates in the form of long, disulfidebonded concatemers, with tens to hundreds of monomers, which mostly adopt a compact, irregularly coiled conformation during normal hemodynamics (12). At sites of hemorrhage, flow changes from shear to elongational. On transition from low to high shear and from shear to elongational flow, irregularly coiled molecules extend to a thread-like shape, and elongational (tensile) force is exerted throughout their lengths (13-16). Molecular elongation exposes the multiple A1 binding sites in VWF concatamers for multivalent binding to GPIbα (9,11,14,(16)(17)(18).In vivo, tensile force transmitted through VWF is applied to the N and C termini of individual domains, and could theoretically change A1 domain conformation before binding to GPIbα. Although this scenario has not yet been observed, single-molecule studies demonstrate two distinct force-dependent dissociation pathways (flex-bond behavior) of the wild-type (WT) A1-GPIbα complex, and thus suggest that two conformational states can be present after formation of the receptor−ligand complex (6).Mutations in VWF cause von Willebrand disease (VWD), the most common human heri...

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Section: Discussionmentioning

confidence: 99%

Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases

Kim

Hudson

Springer

2015

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

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“…Lifetime was measured from the instant the force reached the desired level to the instant of bond dissociation (Fig. 3a, blue and red traces) 30 . To ensure higher possibilities (495%) for single-ligand bond events, we coated Thy-1 at a lower site density (B233 mm À 2 ) in bond lifetime and molecular stiffness analysis than that (B898 mm À 2 ) in adhesion frequency analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Piezoelectric translator control and the image analysis were done on a personal computer using Labview programmes written in-house. Previously described adhesion frequency and force-clamp assays 30 were run as repeated cycles. In each cycle, the target was driven to approach and contact the probe with a 20-pN compressive force for a 0.5-s contact time that allowed for bond formation and then retracted for adhesion detection.…”

Section: Methodsmentioning

confidence: 99%

“…Surprisingly, we find a complex mechanical regulation of adhesive bonds at the single-molecule level: tensile force prolongs the bond lifetime (that is, catch bonds). In contrast to the well-known catch bonds of bimolecular systems, such as cell adhesion receptors (integrins 28,38,39 , selectins 40,41 , glycoprotein Iba 30,42 , E-cadherin 43 and FimH 44 ), the T-cell receptor 31 and cytoskeletal linkages 45,46 , the Thy-1 catch bond is strongly correlated with a bond-stiffening phenotype, termed 'dynamic catch', which partially shifts force to the already engaged but unstretched coreceptor Syn4. Thus, the data reveal a unique, previously unreported class of receptor-ligand bonds whereby force tightens co-receptor engagement that is required for forcemediated adhesion signalling.…”

mentioning

confidence: 98%

“…However, the molecular mechanisms by which mechanical force is transduced into biochemical signals remains obscure 27 . Singlemolecule approaches (that is, the biomembrane force probe (BFP)) have been extensively used to study force regulation of protein-protein interactions, determine protein conformational changes and understand signal initiation [28][29][30][31] , dissecting the relative contribution of individual proteins from complex molecular cohorts 32 . For example, single-molecule studies have elucidated the catch bond behaviour-bonds can be stabilized rather than disrupted by force 33,34 .…”

mentioning

confidence: 99%

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Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex

Fiore

Chen

et al. 2014

Nat Commun

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Cancer cell adhesion to the vascular endothelium is a critical step of tumour metastasis. Endothelial surface molecule Thy-1 (CD90) is implicated in the metastatic process through its interactions with integrins and syndecans. However, how Thy-1 supports cell-cell adhesion in a dynamic mechanical environment is not known. Here we show that Thy-1 supports b 1 integrin-and syndecan-4 (Syn4)-mediated contractility-dependent mechanosignalling of melanoma cells. At the single-molecule level, Thy-1 is capable of independently binding a 5 b 1 integrin and syndecan-4 (Syn4) receptors. However, in the presence of both a 5 b 1 and Syn4, the two receptors bind cooperatively to Thy-1, to form a trimolecular complex. This trimolecular complex displays a unique phenomenon we coin 'dynamic catch', characterized by abrupt bond stiffening followed by the formation of catch bonds, where force prolongs the bond lifetime. Thus, we reveal a new class of trimolecular interactions where force strengthens the synergistic binding of two co-receptors and modulates downstream mechanosignalling.

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Biomembrane force probe (BFP): Design, advancements, and recent applications to live‐cell mechanobiology

et al. 2023

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Mechanical forces play a vital role in biological processes at molecular and cellular levels, significantly impacting various diseases such as cancer, cardiovascular disease, and COVID‐19. Recent advancements in dynamic force spectroscopy (DFS) techniques have enabled the application and measurement of forces and displacements with high resolutions, providing crucial insights into the mechanical pathways underlying these diseases. Among DFS techniques, the biomembrane force probe (BFP) stands out for its ability to measure bond kinetics and cellular mechanosensing with pico‐newton and nano‐meter resolutions. Here, a comprehensive overview of the classical BFP‐DFS setup is presented and key advancements are emphasized, including the development of dual biomembrane force probe (dBFP) and fluorescence biomembrane force probe (fBFP). BFP‐DFS allows us to investigate dynamic bond behaviors on living cells and significantly enhances the understanding of specific ligand‐receptor axes mediated cell mechanosensing. The contributions of BFP‐DFS to the fields of cancer biology, thrombosis, and inflammation are delved into, exploring its potential to elucidate novel therapeutic discoveries. Furthermore, future BFP upgrades aimed at improving output and feasibility are anticipated, emphasizing its growing importance in the field of cell mechanobiology. Although BFP‐DFS remains a niche research modality, its impact on the expanding field of cell mechanobiology is immense.

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The N-terminal Flanking Region of the A1 Domain Regulates the Force-dependent Binding of von Willebrand Factor to Platelet Glycoprotein Ibα

Cited by 93 publications

References 55 publications

Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases

Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases

Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex

Biomembrane force probe (BFP): Design, advancements, and recent applications to live‐cell mechanobiology

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