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The mechanical stability of proteins regulates their translocation rate into the cell nucleus, Prof Sergi Garcia-Manyes, King's College London

Date(s): 19 February 2020
Time: 15:00 - 16:00
Location: PP2 People's Palace, Mile End Campus, Queen Mary University of London
Details:
Prof Sergi Garcia-Manyes
Prof Sergi Garcia-Manyes
The mechanical stability of proteins regulates their translocation rate into the cell nucleus, with Prof Sergi Garcia-Manyes, King’s College London.

Elvira Infante1†, Andrew Stannard1†, Stephanie J. Board1, Palma Rico-Lastres1, Elena Rostkova1, Amy E.M. Beedle1, Ainhoa Lezamiz1, Yong Jian Wang1, Samuel Gulaidi Breen1, Fani Panagaki1, Vinoth Sundar Rajan1, Catherine Shanahan2, Pere Roca-Cusachs3 and Sergi Garcia-Manyes1,4*

1 Department of Physics, Randall Centre for Cell and Molecular Biophysics, and London Centre for Nanotechnology, King’s College London, WC2R 2LS, London, UK.
2 Cardiovascular Division, James Black Centre, King’s College London, London SE5 9NU, UK
3 Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), and University of Barcelona, 08028 Barcelona, Spain
4 The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK


Abstract
The translocation of mechanosensitive transcription factors (TFs) across the nuclear envelope is a crucial step in cellular mechanotransduction. Yet the molecular mechanisms by which mechanical cues control the nuclear shuttling dynamics of TFs through the nuclear pore complex (NPC) to activate gene expression are poorly understood. Here, we show that the nuclear import rate of myocardin-related transcription factor A (MRTFA) — a protein that regulates cytoskeletal dynamics via the activation of the TF serum response factor (SRF) — inversely correlates with the protein’s nanomechanical stability and does not relate to its thermodynamic stability. Tagging MRTFA with mechanically-stable proteins results in the downregulation of SRF-mediated gene expression and subsequent slowing down of cell migration. We conclude that the mechanical unfolding of proteins regulates their nuclear translocation rate through the NPC and highlight the role of the NPC as a selective mechanosensor able to discriminate forces as low as ?10 pN. The modulation of the mechanical stability of TFs may represent a new, general strategy for the control of gene expression.
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