Tension Enhances the Binding Affinity of β1 Integrin by Clamping Talin Tightly: An Insight from Steered Molecular Dynamics Simulations

Abstract

Integrin activation is a predominant step for cell–cell and cell–ECM interactions. Talin and Kindlin are mechanosensitive adaptor proteins that bind to the integrin cytoplasmic tail and mediate integrin activation, cytoskeleton rearrangement, and focal adhesion assembly. However, knowledge about how Talin and Kindlin synergistically assist integrin activation remains unclear. Here, we performed so-called “ramp-clamp” SMD simulations, which modeled the mechanosignaling from Kindlin, to investigate the effect of tension on the interaction of the β1 integrin cytoplasmic tail with the Talin-F3 domain. The present results showed that mild but not excessive stretching enhanced the binding of integrin with Talin. This mechanical regulation on integrin affinity to Talin referred to an event cascade, in which under stretching, the integrin cytoplasmic tail adopted allostery in response to the mechanical stimulus, remodeling of integrin in favor of Talin-association ensued, and finally, a stable, close-knit complex was formed. In the cascade, the torsion angle transition of integrin was the cue for the stable interaction of the complex under tensile force. The present work suggested a model for Talin and Kindlin to synergistically activate integrin. It should help understand integrin activation and its mechanochemical regulation mechanism, integrin-related innate cellular immune responses, cell adhesion, cell–cell interaction, and integrin-related drug development.

MD Simulation Reveals Regulation of Mechanical Force and Extracellular Domain 2 on Binding of DNAM-1 to CD155

“…However, there might be a significant gap between the results from the MD simulation and the data measured with single molecular tools, such as atomic force microscopy (AFM), optical and magnetic tweezers [ 29 ], coming from effects of timescale on predicting ligand–receptor interactions with a timescale of about 0.01–1.00 s by MD simulation of about 100 ns. Regardless of the timescale effect on complex dissociation , it was expected here that , the mechano-regulation factor or the normalized complex dissociation probability, should be comparable with experimental data if the conformations sampled from the simulation are perfect [ 22 , 24 ].…”

“…The mechano-sensitive proteins, such as integrins, selectins, and other transmembrane receptors/ligands, have been reported to have the force-induced changes of conformations and functions [ 18 , 19 , 20 , 21 ]; these changes will enhance or reduce subsequent transmembrane signaling, cell–cell interactions, and cellular biological processes [ 19 , 22 , 23 ]. It hints that a force-dependent interaction between DNAM-1 and CD155 may be required in mediating the involved cellular events in mechano-microenvironment, such as substrate rigidity, blood vessel extension, blood flow shear force, and so on [ 19 , 24 , 25 ]. However, the role of D2 and the mechanical regulation of DNAM-1′s interaction with CD155 remain unclear.…”

Research progress of non-coding RNA-mediated regulation of the osteogenesis of periodontal tissues when mechanical tension is applied

“…The receptors that respond to tension can be divided into two types; proximal mechanoreceptors that include integrins, primary cilia, ion channels, and cytoskeleton, and nuclear membrane proteins. Integrin is a heterogeneous dimer composed of α and β subunits, which senses extracellular matrix stimulation in a non-covalent manner by binding with extracellular ligands which results in a conformation change, and thus transmits a mechanical signal [16]. Talin and kindlin are mechanosensitive adaptor proteins, which bind with the integrin cytoplasmic tail.…”

Integrin Mechanosensing relies on Pivot-clip Mechanism to Reinforce Cell Adhesion

“…While the current hypothesis states that binding between FN and 𝛼 5 𝛽 1 triggers an opening of integrin's cytoplasmic tails leading to an accumulation of adaptor proteins that resist cell-matrix forces (Figure 6), further studies are needed to elucidate the mechanism behind integrin activation. Multiple steered MD models have been employed to interrogate 𝛽 3 integrin activation (22,44,(54)(55)(56)(57), with few investigating the cytoplasmic end of 𝛽 1 integrin (58,59). However, to our knowledge, our approach is unique in that we model the interface between FN and the 𝛼 5 𝛽 1 integrin heads, where forces are transmitted bidrectionally between the cell and its matrix.…”