How cells control their borders

Date:
March 28, 2022
Source:
University of Groningen
Summary:
Bacteria and yeast need to prevent leakage of numerous small
molecules through their cell membrane. Biochemists have studied how
the composition of the membrane affects passive diffusion and the
robustness of this membrane. Their results could help the biotech
industry to optimize microbial production of useful molecules and
help in drug design.



FULL STORY ========================================================================== Bacteria, fungi, and yeast are very good at excreting useful substances
such as weak acids. One way in which they do this is through passive
diffusion of molecules across the cell membrane. At the same time, cells
need to prevent leakage of numerous small molecules. Yeast cells, for
instance, can live in hostile environments thanks to a very robust and relatively impermeable membrane system. Biochemists at the University
of Groningen, the Netherlands, have studied how the composition of
the membrane affects passive diffusion and the robustness of the cell
membrane. Their results, which were published in Nature Communications 25 March, could help the biotech industry to optimize microbial production
of useful molecules and help in drug design.


========================================================================== Border control is very important to cells. Their membranes separate the
inner and outer environments, which are quite different. To absorb useful compounds, such as nutrients, or to excrete waste, cells can use selective transport systems. However, some transport across the membrane takes
place by passive diffusion. This is a non-selective process that will let
some molecules go in or out, depending on their size and hydrophobicity,
for example. Active transporters have been studied extensively; however,
our knowledge of passive diffusion through the membrane is still very incomplete.

Synthetic vesicles This is a problem for the biotechnology industry, which
uses cells as factories to produce a myriad of useful substances and that
needs these worker cells to survive under harsh conditions, for example
in an environment with high alcohol or weak acid concentrations. Bert
Poolman, Professor of Biochemistry at the University of Groningen, was approached by a biotech company that was interested in producing lactic
acid in bacteria. They wanted to know more about passive diffusion. This
fitted in nicely with another project that Poolman is working on. 'We
are highly interested in these passive transport processes because of our involvement in a project to build a synthetic cell,' says Poolman. 'If you
can use passive diffusion instead of an active transport system, you need
fewer parts to construct such a cell.' So, he combined both questions
in a research project. 'We started out with a systematic study of what
causes the differences in permeability of yeast membranes and bacterial membranes,' says Poolman. His team created synthetic vesicles that were
made up of three to four different lipids. Ergosterol or cholesterol was
added to the membranes to affect their fluidity and rigidity. A range of
small molecules was tested using this system and the results from these experiments guided molecular dynamic simulations of diffusion through membranes. The in-silico studies, supervised by Professor Siewert-Jan
Marrink, provided a deeper insight into the molecular mechanism of
diffusion.

Tweaking The fatty acid tails of the lipids turned out to be most
important in determining the properties of membranes, whereas the
hydrophilic head groups had little effect on the permeability. The length
of the tails also mattered.

'And saturated tails, with no double carbon bonds, are stiffer than
unsaturated ones. Hydrophobic interactions cause a close packing of
these tails, resulting in a gel phase that is not very penetrable,'
explains Poolman. Sterols increase the fluidity but in the case of yeast,
which uses ergosterol, the permeability remains low. 'Thus, by tweaking
the saturation of the fatty acids and the type and amount of sterol in
the membrane, we can modify the permeability of the plasma membrane of
yeast and bacterial cells.' Poolman and his colleagues have, therefore, defined a number of variables that alter the permeability of membranes
for different classes of compounds. This information can be used by
companies that use yeasts or bacteria as cell factories. 'However, our
results cannot be directly applied to those cells,' warns Poolman. 'Real membranes contain hundreds of different lipids and the composition can
vary between different locations in the membrane. In addition, these
cell membranes contain all kinds of proteins. If you make changes in,
for example, the lipid composition of the membrane, a lot can go wrong
and the function of a membrane protein can be affected.' Drug design The increased understanding of the physical processes that affect permeability
can help companies to understand why certain cells are better for specific processes than others. 'The usual way to tweak strains is by directed evolution. Our results will help companies to better understand the
results of those optimizations and guide their cell engineering efforts.' Another application is the design of drugs that act inside cells.

'Pharmaceutical companies use a set of empirically established rules
to optimize drugs for action inside cells, based on parameters such as
size or polarity. Our study highlights the importance of the membrane composition of the targeted cells and this could help in drug design.'

========================================================================== Story Source: Materials provided by University_of_Groningen. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jacopo Frallicciardi, Josef Melcr, Pareskevi Siginou, Siewert
J. Marrink,
Bert Poolman. Membrane thickness, lipid phase and sterol type
are determining factors in the permeability of membranes to small
solutes.

Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-29272-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220328112432.htm

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