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 February 12, 2018

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

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. Although this study has recently been challenged:

    Have your say

    Your email address will not be published. Required fields are marked *

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

    Register here

    Also in the cell biology category:

    Nuclear envelope assembly defects link mitotic errors to chromothripsis

    Shiwei Liu, Mijung Kwon, Mark Mannino, et al.

    Selected by Gautam Dey

    A 3D model of human skeletal muscle innervated with stem cell-derived motor neurons enables epsilon-subunit targeted myasthenic syndrome studies

    Mohsen Afshar Bakooshli, Ethan S Lippmann, Ben Mulcahy, et al.

    Selected by Chris Demers

    Stopping Transformed Growth with Cytoskeletal Proteins: Turning a Devil into an Angel

    Bo Yang, Haguy Wolfenson, Naotaka Nakazawa, et al.

    Selected by Jon Humphries

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

    Andrew S LaCroix, Andrew D Lynch, Matthew E Berginski, et al.

    Selected by Amanda Haage


    Persistent cell motility requires transcriptional feedback of cytoskeletal – focal adhesion equilibrium by YAP/TAZ

    Devon E Mason, James H Dawahare, Trung Dung Nguyen, et al.

    Selected by Carla Mulas


    Dynamin-2 facilitates Atg9 recycling from nascent autophagosomes

    Alejandro Martorell Riera, Cinta Iriondo Martinez, Samuel Itskanov, et al.

    Selected by Justin Joachim

    Focal adhesion kinase regulates early steps of myofibrillogenesis in cardiomyocytes

    Nilay Taneja, Abigail C Neininger, Matthew R Bersi, et al.

    Selected by Vassilis Papalazarou

    Content-Aware Image Restoration: Pushing the Limits of Fluorescence Microscopy

    Martin Weigert, Uwe Schmidt, Tobias Boothe, et al.

    Selected by Uri Manor

    Reticular adhesions: A new class of adhesion complex that mediates cell-matrix attachment during mitosis

    John G Lock, Matthew C Jones, Janet A Askari, et al.

    Selected by Guillaume Jacquemet

    In vivo topology converts competition for cell-matrix adhesion into directional migration

    Fernanda Bajanca, Nadege Gouignard, Charlotte Colle, et al.

    Selected by Helen Zenner

    The expa1-1 mutant reveals a new biophysical lateral root organogenesis checkpoint

    Priya Ramakrishna, Graham A. Rance, Lam D. Vu, et al.

    Selected by Annika Weimer


    F-actin patches nucleated on chromosomes coordinate capture by microtubules in oocyte meiosis

    Mariia Burdyniuk, Andrea Callegari, Masashi Mori, et al.

    Selected by Binyam Mogessie

    Heterochromatin drives organization of conventional and inverted nuclei

    Martin Falk, Yana Feodorova, Natasha Naumova, et al.

    Selected by Boyan Bonev

    Comprehensive characterization of transcript diversity at the human NODAL locus

    Scott D Findlay, Lynne-Marie Postovit

    Selected by Christian Ramos

    Cell-matrix adhesion controls Golgi organization and function by regulating Arf1 activation in anchorage-dependent cells.

    Vibha Singh, Chaitanya Erady, Nagaraj Balasubramanian

    Selected by Nicola Stevenson

    Polarization of Myosin II refines tissue material properties to buffer mechanical stress.

    Maria Duda, Nargess Khalilgharibi, Nicolas Carpi, et al.

    Selected by Yara E. Sánchez Corrales

    We want to make our website, and the services we provide, useful and reliable. This sometimes involves placing small amounts of information called cookies on the device you used to access the internet. If you continue to use this website we will assume you are happy to accept our cookies.