Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/027888

Extracellular Forces Cause the Nucleus to Deform in a Highly Controlled Anisotropic Manner

Kristina Haase·Joan K. L. Macadangdang·Claire H. Edrington·Charles M. Cuerrier·Sebastian Hadjiantoniou·James L. Harden·Ilona S. Skerjanc·Andrew E. Pelling
View original source ↗Export metadata ↓

Abstract

Physical forces arising in the extra-cellular environment have a profound impact on cell fate and gene regulation; however the underlying biophysical mechanisms that control this sensitivity remain elusive. It is hypothesized that gene expression may be influenced by the physical deformation of the nucleus in response to force. Here, using 3T3s as a model, we demonstrate that extra-cellular forces cause cell nuclei to rapidly deform (< 1 s) preferentially along their shorter nuclear axis, in an anisotropic manner. Nuclear anisotropy is shown to be regulated by the cytoskeleton within intact cells, with actin and microtubules resistant to orthonormal strains. Importantly, nuclear anisotropy is intrinsic, and observed in isolated nuclei. The sensitivity of this behaviour is influenced by chromatin organization and lamin-A expression. An anisotropic response to force was also highly conserved amongst an array of examined nuclei from differentiated and undifferentiated cell types. Although the functional purpose of this conserved material property remains elusive, it may provide a mechanism through which mechanical cues in the microenvironment are rapidly transmitted to the genome.

Source connections

Explore related subjects

BiophysicsPreprint

Keep this discovery

BibTeXRIS

Kristina Haase, Joan K. L. Macadangdang, Claire H. Edrington, Charles M. Cuerrier, Sebastian Hadjiantoniou, James L. Harden, Ilona S. Skerjanc, Andrew E. Pelling. 2015-10-01. Extracellular Forces Cause the Nucleus to Deform in a Highly Controlled Anisotropic Manner. https://doi.org/10.1101/027888

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2016

TatA complexes exhibit a marked change in organisation in response to expression of the TatBC complex

The twin arginine translocation (Tat) system is an integral membrane protein complex that accomplishes the remarkable feat of transporting large, fully-folded polypeptides across the inner membrane of bacteria, into the periplasm. In Escherichia coli Tat is comprised of three membrane proteins: TatA, TatB and TatC. How these proteins arrange themselves in the inner membrane to permit passage of Tat substrates, whilst maintaining membrane integrity, is still poorly understood. TatA is the most abundant component of this complex and facilitates assembly of the transport mechanism. We have utilised immunogold labelling in combination with array tomography to gain insight into the localisation and distribution of the TatA protein in E. coli cells. We show that TatA exhibits a uniform distribution throughout the inner membrane of E. coli and that altering the expression of TatBC shows a previously uncharacterised distribution of TatA in the inner membrane. Array tomography was used to provide our first insight into this altered distribution of TatA in 3D space, revealing that this protein forms linear clusters in the inner membrane of E. coli upon increased expression of TatBC. This is the first indication that TatA organisation in the inner membrane alters in response to changes in Tat subunit stoichiometry.\n\nSummary statementThe volumetric electron-microscopy technique, array tomography, revealed a novel distribution of TatA protein (from the twin arginine translocase complex), in Escherichia coli.

Biophysics↗
bioRxiv2016

A unified coarse-grained theory of bacterial physiology explains the relationship between cell size, growth rate and proteome composition under various growth limitations

Universal observations in Biology are sometimes described as "laws". In E. coli, experimental studies performed over the past six decades have revealed major growth laws relating ribosomal mass fraction and cell size to the growth rate. Because they formalize complex emerging principles in biology, growth laws have been instrumental in shaping our understanding of bacterial physiology. Here, we discovered a novel size law that connects cell size to the inverse of the metabolic proteome mass fraction and the active fraction of ribosomes. We used a simple whole-cell coarse-grained model of cell physiology that combines the proteome allocation theory and the structural model of cell division. The model captures all available experimental data connecting the cell proteome composition, ribosome activity, division size and growth rate in response to nutrient quality, antibiotic treatment and increased protein burden. Finally, a stochastic extension of the model explains non-trivial correlations observed in single cell experiments including the adder principle. This work provides a simple and robust theoretical framework for studying the fundamental principles of cell size determination in unicellular organisms.

Biophysics↗
bioRxiv2016

Identification of a Zika NS2B-NS3pro pocket susceptible to allosteric inhibition by small molecules including qucertin rich in edible plants

It has been recently estimated that one-third of the world population will be infected by Zika virus, but unfortunately so far there is no vaccine or medicine available. In particular, the special concern on the vaccine treatment to Zika and Dengue arising from antibody-dependent enhancement strongly emphasizes the irreplaceable role of its NS2B-NS3 protease (NS2B-NS3pro) as a target for anti-Zika drug discovery/design due to its absolutely-essential role in viral replication. Very recently we identified two small molecules inhibit Zika NS2B-NS3pro in non-competitive mode, with Ki values of 0.57 and 2.02 {micro}M respective for p-Nitrophenyl-p-guanidino benzoate and qucertin. Here, by molecular docking, we show that although one is designed compound while another is a natural product, both molecules bind to the same pocket on the back of the substrate-binding pocket of Zika NS2B-NS3pro. As the two inhibitors fundamentally differ from cn-716, the only known peptidomimetic boronic acid inhibitor in both structure scaffolds and inhibitory modes, our discovery might open up a new avenue for the future development of allosteric inhibitors, which is highly demanded to achieve therapeutic inhibition of flaviviral NS2B-NS3pro complexes. Furthermore, as qucertin is abundant in many vegetables and fruits such caper, lovage, tea and red onion, our results should benefit the public to immediately fight Zika virus.

Biophysics↗