Mechanical regulation of talin through binding and history-dependent unfolding

Dahal, Narayan; Sharma, Sabita; Phan, Binh; Eis, Annie; Popa, Ionel

doi:10.1126/sciadv.abl7719

Cited by 14 publications

(7 citation statements)

References 58 publications

(83 reference statements)

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“…This interplay between talin nanomechanics and binding was also demonstrated with another key talin partner, deleted-in-cancer-1 (DLC1). DLC1 binds to the folded talin R8 domain, which suddenly gains an outstanding mechanical stability that makes it inextensible even under forces in excess of 100 pN 61 , similar to the binding-induced mechanical stabilization of other non-force-sensing proteins 62 , 63 . However, different from the effect DLC1 binding has on talin mechanics, our study shifts the focus to the impact binding under force has on the binding protein.…”

Section: Discussionmentioning

confidence: 99%

Allosteric activation of vinculin by talin

et al. 2023

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The talin-vinculin axis is a key mechanosensing component of cellular focal adhesions. How talin and vinculin respond to forces and regulate one another remains unclear. By combining single-molecule magnetic tweezers experiments, Molecular Dynamics simulations, actin-bundling assays, and adhesion assembly experiments in live cells, we here describe a two-ways allosteric network within vinculin as a regulator of the talin-vinculin interaction. We directly observe a maturation process of vinculin upon talin binding, which reinforces the binding to talin at a rate of 0.03 s−1. This allosteric transition can compete with force-induced dissociation of vinculin from talin only at forces up to 10 pN. Mimicking the allosteric activation by mutation yields a vinculin molecule that bundles actin and localizes to focal adhesions in a force-independent manner. Hence, the allosteric switch confines talin-vinculin interactions and focal adhesion build-up to intermediate force levels. The ‘allosteric vinculin mutant’ is a valuable molecular tool to further dissect the mechanical and biochemical signalling circuits at focal adhesions and elsewhere.

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Section: Discussionmentioning

confidence: 99%

Allosteric activation of vinculin by talin

et al. 2023

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“…In this theory, these switch patterns represent a binary code the cell uses to spatially organise the enzymatic processes in the synapse to coordinate synaptic activity (Ball et al, 2024;Barnett and Goult, 2022). Currently, the role of talin in synaptic regulation and memory is not well studied, however, the role of talin in mechanical memory in other systems has been demonstrated experimentally (Dahal et al, 2022;Marhuenda et al, 2023).…”

Section: Synaptic Adhesion and Mechanical Signallingmentioning

confidence: 99%

The structure of an Amyloid Precursor Protein/talin complex indicates a mechanical basis of Alzheimer's Disease.

Ellis,

Ward,

Rice

et al. 2024

Preprint

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Misprocessing of Amyloid Precursor Protein (APP) is one of the major causes of Alzheimer's disease. APP is a transmembrane protein comprising a large extracellular region, a single transmembrane helix and a short cytoplasmic tail containing an NPxY motif (normally referred to as the YENPTY motif). Talin is a synaptic scaffold protein that connects the cytoskeletal machinery to the plasma membrane via binding to one of two highly conserved NPxY motifs in the cytoplasmic tail of integrin transmembrane receptors. Here we report the crystal structure of an APP/talin complex identifying a new way to couple the cytoskeletal machinery to synaptic sites via APP. Structural modelling reveals that APP forms an extracellular meshwork that mechanically couples the cytoskeletal meshworks of both the pre-, and post-synaptic compartments. In this context, we propose APP processing as a mechanical signalling pathway with similarities to Notch signalling, whereby the cleavage sites in APP represent mechanical sensors, with varying accessibility to cleavage by secretases. During synaptogenesis in healthy neurons, the APP/talin linkage would provide an exquisite mechanical coupling between synapses, with tightly controlled APP processing providing instructions to maintain this synchrony. Furthermore, APP directly coupling to the binary switches in talin indicates a role for APP in mechanical memory storage as postulated by the MeshCODE theory. The implication that APP is a regulator of mechanical signalling leads to a new hypothesis for Alzheimer's disease, where mis-regulation of APP dynamics results in loss of mechanical integrity of the synapse, corruption and loss of mechanical binary data, and excessive generation of the toxic plaque-forming Aβ42 peptide. In support of this model, we show that talin1 depletion has a dramatic effect on APP processing in cells. Much needs to be done to experimentally validate this idea, but we present here a novel theory of Alzheimer's Disease with a role for APP in the mechanically coded binary information storage in the synapse, which identifies a potential novel therapeutic strategy for treating Alzheimer's Disease.

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“…In contrast to AFM and optical tweezers, magnetic tweezers have only recently been implemented to study protein dynamics under force 37 , 38 , 40 , 55 , 64 , 65 . An inherent advantage of magnetic tweezers for measuring protein dynamics is its intrinsic force-clamp conditions, which allow for direct manipulation of the pulling force without requiring external force-feedback systems, hence enabling the equilibrium measurement.…”

Section: Advantages and Limitationsmentioning

confidence: 99%

Single-molecule magnetic tweezers to probe the equilibrium dynamics of individual proteins at physiologically relevant forces and timescales

Tapia-Rojo,

Mora,

Garcia-Manyes

2024

Nat Protoc

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Published version. It is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details for citations. Rights & PermissionsWe apply a non-exclusive, irrevocable, worldwide CC-BY license on all author accepted manuscripts describing work carried out at the Francis Crick Institute. This allows authors to share the manuscript with colleagues, use it in teaching and deposit it in repositories.

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Mechanical regulation of talin through binding and history-dependent unfolding

Cited by 14 publications

References 58 publications

Allosteric activation of vinculin by talin

Allosteric activation of vinculin by talin

The structure of an Amyloid Precursor Protein/talin complex indicates a mechanical basis of Alzheimer's Disease.

Single-molecule magnetic tweezers to probe the equilibrium dynamics of individual proteins at physiologically relevant forces and timescales

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