Close

Tunable molecular tension sensors reveal extension-based control of vinculin loading

Andrew S LaCroix, Andrew D Lynch, Matthew E Berginski, Brenton D Hoffman

Preprint posted on 12 February 2018 https://www.biorxiv.org/content/early/2018/02/12/264549

Article now published in eLife at http://dx.doi.org/10.7554/elife.33927

The tension sensors of the future - better optimized genetically encoded probes reveal novel mechanistic detail in how mechanotransduction works

Selected by Amanda Haage

Categories: biophysics, cell biology

Why This Is CoolIt is now widely accepted that besides responding to chemical cues in their environment, cells also participate in mechanotransduction, a process by which they sense and respond to physical aspects of the environment (i.e. matrix stiffness or shear stress, etc.). The main way cells do this is through mechanosensitive signaling or the conformational change of load-bearing proteins in response to force. The main way this has been studied is through FRET-based tension sensors that are genetically encoded into those load-bearing proteins. The problem addressed by this work is that to date, the design of these tension sensors has been based on models created in cell-free systems, but they are then exclusively used in cells. Here they provide a novel and validated method for predicting tension sensor sensitivity in cells. This allows them to create an optimized tension sensor for the load-bearing protein vinculin that is determined to be 300% better by their calculations. They use this optimized sensor to demonstrate a gradient of forces across focal adhesions at the cell periphery. They are also able to use sensors of varying length to determine that protein extension, rather than the force experienced by the protein, may be the major mechanism of mechanical signaling in cells. This work provides an incredibly useful tool in mapping out the future of precise new sensor design. It demonstrates the usefulness of optimized sensors to uncover new mechanisms of mechanical signaling.

 

Fig. 1 – (A) Design and characterization of tunable FRET-based molecular tension sensors. Sensor function depends on the Förster radius of the chosen FRET pair (B) as well as the length (C) and stiffness (D) of the extensible polypeptide domain.

 

Why I Selected ItI think the model presented here will quickly be adopted as the new standard in molecular tension sensor design. They have essentially eliminated the previous system of designing that was based on literature guesswork and then checking if sensors work through extensive cellular characterization. As someone interested in mechanobiology, I look forward to seeing a new crop of tension sensors that are designed based on this model and expanded to other load-bearing proteins.

 Open Questions

  • Are there any reasons the principles of tension sensor design discussed here could not be expanded to proteins other than vinculin?
  • In which cellular contexts would either an extension- or force-based control mechanism be more advantageous? Why would this be a context-specific way to modulate mechanical signaling?
  • Will tension sensors ever be useful in vivo?

Related Research

  • The first calibrated genetically-encoded molecular tension sensor module & the original vinculin tension sensor
    • Grashoff, C., Hoffman, B. D., Brenner, M. D., Zhou, R., Parsons, M., Yang, M. T., McLean, M. A., Sligar, S. G., Chen, C. S., Ha, T., Schwartz, M. A. (2010). Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature, 466: 263-266. doi:10.1038/nature09198
  • Review of the field and current limitations
    • Freikamp, A., Mehlich, A., Klingner, C., Grashoff, C. (2016b). Investigating piconewton forces in cells by FRET-based molecular force microscopy. J Struct Biol. doi:10.1016/j.jsb.2016.03.011

 

Tags: cell-ecm adhesion, mechanotransduction, protein biology

Posted on: 4 March 2018

Read preprint (No Ratings Yet)

Author's response

Brent Hoffman shared

  1. The new modules can be applied to any existing tension sensor. There are always challenges associated with making a tension sensor for a new protein, as a significant number of controls have to be done to ensure that the insertion of the tension sensing module does not affect the function of the protein to be studied. In this regard, the modules developed in this work have all the same issues as the other published modules.
  2. Great question. We are working on it now
  3. While not our work, there are several examples of the tension sensor being useful in vivo. Here are two examples. Some of the papers are quite recent.
    1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118667/. Although this study has recently been challenged: https://www.nature.com/articles/s41598-017-14136-y
    2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680264/

Have your say

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

Also in the cell biology category:

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria

 



List by Dey Lab, Samantha Seah

1

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

 



List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

 



List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Dey Lab

MitoList

This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

 



List by Sandra Franco Iborra

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.

 



List by Dey Lab, Amanda Haage
Close