Multi-level Force-dependent Allosteric Enhancement of αE-catenin Binding to F-actin by Vinculin

Bax, Nicolas A.; Wang, Amy; Huang, Derek; Pokutta, Sabine; Weis, William I.; Dunn, Alexander R.

doi:10.1016/j.jmb.2023.167969

Cited by 5 publications

(3 citation statements)

References 70 publications

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“…Although Vinculin does not affect the binding rate between Jub and the N domain of α-catenin, it does inhibit the folding process of the M1 domain of α-catenin. In addition, Vinculin can also exhibit a force-dependent enhancement of α-catenin binding to F-actin in that association of Vinculin with the ternary complex of E-cadherin, β-catenin, and αE-catenin increases the bound lifetime of individual complexes on F-actin as a function of the number of load-bearing complexes bound but only when force is directed toward the pointed end of the filament [83].…”

Section: The Structure Of α-Cateninmentioning

confidence: 99%

The Interaction of Mechanics and the Hippo Pathway in Drosophila melanogaster

Gou,

Zhang,

Othmer

2023

Cancers

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Drosophila melanogaster has emerged as an ideal system for studying the networks that control tissue development and homeostasis and, given the similarity of the pathways involved, controlled and uncontrolled growth in mammalian systems. The signaling pathways used in patterning the Drosophila wing disc are well known and result in the emergence of interaction of these pathways with the Hippo signaling pathway, which plays a central role in controlling cell proliferation and apoptosis. Mechanical effects are another major factor in the control of growth, but far less is known about how they exert their control. Herein, we develop a mathematical model that integrates the mechanical interactions between cells, which occur via adherens and tight junctions, with the intracellular actin network and the Hippo pathway so as to better understand cell-autonomous and non-autonomous control of growth in response to mechanical forces.

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Section: The Structure Of α-Cateninmentioning

confidence: 99%

The Interaction of Mechanics and the Hippo Pathway in Drosophila melanogaster

Gou,

Zhang,

Othmer

2023

Cancers

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“…How these seemingly contradictory properties are achieved at the molecular level is in general poorly understood. Although previous studies have examined how the components of cadherin-mediated adherens junctions respond to mechanical load [6][7][8][9][10][11][12][13] , much less is known about how the other adhesion complexes present at cell-cell junctions may respond to force 14 . Unlike the cadherin-catenin complex, most other cell-cell adhesion complexes contain a cytoskeletal linker protein containing at least one PDZ domain 1 .…”

Section: Introductionmentioning

confidence: 99%

PDZ Domains from the Junctional Proteins Afadin and ZO-1 Act as Mechanosensors

Vachharajani,

DeJong,

Dunn

2023

Preprint

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Intercellular adhesion complexes must withstand mechanical forces to maintain tissue cohesion, while also retaining the capacity for dynamic remodeling during tissue morphogenesis and repair. Most cell-cell adhesion complexes contain at least one PSD95/Dlg/ZO-1 (PDZ) domain situated between the adhesion molecule and the actin cytoskeleton. However, PDZ-mediated interactions are characteristically nonspecific, weak, and transient, with several binding partners per PDZ domain, micromolar dissociation constants, and bond lifetimes of seconds or less. Here, we demonstrate that the bonds between the PDZ domain of the cytoskeletal adaptor protein afadin and the intracellular domains of the adhesion molecules nectin-1 and JAM-A form molecular catch bonds that reinforce in response to mechanical load. In contrast, the bond between the PDZ3-SH3-GUK (PSG) domain of the cytoskeletal adaptor ZO-1 and the JAM-A intracellular domain becomes dramatically weaker in response to ~2 pN of load, the amount generated by single molecules of the cytoskeletal motor protein myosin II. These results suggest that PDZ domains can serve as force-responsive mechanical anchors at cell-cell adhesion complexes, and that mechanical load can enhance the selectivity of PDZ-peptide interactions. PDZ mechanosensitivity may thus help to generate the intricate molecular organization of cell-cell junctions and allow junctional complexes to dynamically remodel in response to mechanical load.

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“…Growing data suggest that mechanical forces alter the binding between proteins in non-intuitive ways (2,17,18). For example, several of the F-actin binding proteins in cell adhesion (α-catenin, talin, vinculin) have been found to display catch bond behavior, where force increases their binding to F-actin, especially when pulled towards the pointed end of F-actin (19)(20)(21)(22). Moreover, domains in talin and α-catenin can be mechanically unfolded to reveal cryptic binding motifs that are not accessible to binding partners when folded but, when unfolded, can selectively recruit proteins such as vinculin to strengthen focal adhesions (23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

A mechanical circuit in End4p coordinates force transmission during clathrin-mediated endocytosis

Ren,

Yang,

Fujita

et al. 2023

Preprint

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Mechanical forces are transmitted from the actin cytoskeleton to the membrane during clathrin-mediated endocytosis (CME) in the fission yeast Schizosaccharomyces pombe. The onset and termination of force transmission is tightly regulated temporally during different stages of CME, and spatially over the surface of the invaginated membrane. How force transmission is regulated and coordinated at the molecular scale is unclear. An adaptor protein in CME, End4p, directly transmits force by binding to both the membrane (through ANTH domain) and F-actin (through THATCH domain). We show that 8pN is required for stable binding between THATCH and F-actin. We also report the discovery and characterization of a new domain on End4p, which we named Rend (R domain in End4p), that resembles R12 of talin. Membrane localization of Rend primes the binding of THATCH to F-actin, and force-induced unfolding of Rend at 15pN terminates the transmission of force during CME. We show that the mechanical properties (mechanical stability, unfolding length, hysteresis) of Rend and THATCH are tuned to form an auto-regulated circuit for the initiation, transmission and termination of force between the actin cytoskeleton and membrane. Shorting the circuit leads to permanent End4p association with the membrane or with F-actin, or failure to enter the force transmission cycle. Mathematical modeling of force transmission through Rend-THATCH connection shows that input force from F-actin is buffered to a narrow range towards the membrane. The mechanical circuit by Rend and THATCH may be conserved and coopted evolutionarily in cell adhesion complexes.

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Multi-level Force-dependent Allosteric Enhancement of αE-catenin Binding to F-actin by Vinculin

Cited by 5 publications

References 70 publications

The Interaction of Mechanics and the Hippo Pathway in Drosophila melanogaster

The Interaction of Mechanics and the Hippo Pathway in Drosophila melanogaster

PDZ Domains from the Junctional Proteins Afadin and ZO-1 Act as Mechanosensors

A mechanical circuit in End4p coordinates force transmission during clathrin-mediated endocytosis

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