Fast force loading disrupts molecular binding stability in human and mouse cell adhesions

Yunfeng Chen, Jiexi Liao, Zhou Yuan, Kaitao Li, Baoyu Liu, Lining Arnold Ju, Cheng Zhu

Research output: Contribution to journalArticlepeer-review

Abstract

Force plays critical roles in cell adhesion and mechano-signaling, partially by regulating the dissociation rate, i.e., off-rate, of receptor-ligand bonds. However, the mechanism of such regulation still remains elusive. As a controversial topic of the field, when measuring the “off-rate vs. force” relation of the same molecular system, different dynamic force spectroscopy (DFS) assays (namely, force-clamp and force-ramp assays) often yield contradictive results. Such discrepancies hurdled our further understanding of molecular binding, and casted doubt on the existing theoretical models. In this work, we used a live-cell DFS technique, biomembrane force probe, to measure the single-bond dissociation in three receptor-ligand systems which respectively have important functions in vascular and immune systems: human platelet GPIbα-VWF, mouse T cell receptor-OVA peptide:MHC, and mouse platelet integrin αIIbβ3-fibrinogen. Using force-clamp and force-ramp assays in parallel, we identified that the force loading disrupted the stability of molecular bonds in a rate-dependent manner. This disruptive effect was achieved by the transitioning of bonds between two dissociation states: faster force loading induces more bonds to adopt the fast-dissociating state (and less to adopt the slow-dissociating state). Based on this mechanism, a new biophysical model of bond dissociation was established which took into account the effects of both force magnitude and loading rate. Remarkably, this model reconciled the results from the two assays in all three molecular systems under study. Our discoveries provided a new paradigm for understanding how force regulates receptor-ligand interactions and a guideline for the proper use of DFS technologies. Furthermore, our work highlighted the opportunity of using different DFS assays to answer specific biological questions in the field of cell adhesion and mechano-signaling.

Original languageEnglish (US)
Pages (from-to)211-223
Number of pages13
JournalMCB Molecular and Cellular Biomechanics
Volume16
Issue number3
DOIs
StatePublished - 2019
Externally publishedYes

Keywords

  • Biophysical model
  • Cell adhesion
  • Dynamic force spectroscopy
  • Force-regulated molecular binding
  • Mechano-signaling

ASJC Scopus subject areas

  • Biophysics
  • Molecular Medicine
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Fast force loading disrupts molecular binding stability in human and mouse cell adhesions'. Together they form a unique fingerprint.

Cite this