Harnessing the organization of the cell surface

Date:
December 2, 2021
Source:
ETH Zurich
Summary:
Scientists have developed a new method to determine how proteins
are organized on the surface of cells. Insights gained with the
technology could lead to the development of novel drugs to fight
cancer.



FULL STORY ========================================================================== Biological cells have multiple functions, and they need to communicate
with each other to coordinate them. Molecules on the cell surface are
central to this process. For decades, biologists have been studying
such surface proteins and it is becoming increasingly clear that not
only their presence but also their organisation on the cell's surface
is crucial to the function of a cell.


========================================================================== "Proteins aren't simply distributed evenly and independently of one
another across the cell's surface; instead, they're organised into
molecular communities. In these communities, proteins often work together
to fulfil cellular functions," explains Bernd Wollscheid, Professor at
ETH Zurich's Institute of Translational Medicine. Together with a large interdisciplinary team that includes further researchers from ETH Zurich
and other institutions, Wollscheid's doctoral student Maik Mu"ller has
now developed a technology that can be used to discover the organisation
of cell surface molecules.

"Who got a kiss?" With this technology called LUX-MS, the researchers
can determine with nanometer-scale precision how proteins integrate into
an organisation on the cell surface -- in other words, which proteins
are in proximity to each other.

So far, scientists were able to measure interactions of individual
proteins that have a high affinity for each other, as well as for
molecules that reside inside the cell. However, the new method is the
first to enable scientists to specifically detect the organisation of
the entirety of cell surface molecules.

Wollscheid refers to this entirety as the "surfaceome." The term is
composed of the word "surface" and the suffix "-ome," that is also used
in terms such as genome or proteome.

With a twinkle in his eye, Wollscheid explains the principle behind the
method as follows: "We specifically modify a particular surface molecule
so that it likes to 'give kisses' to molecules in its proximity, and
then we check the other surface molecules for traces of lipstick." In
more technical terms, a small chemical compound is attached to a protein
of interest. When irradiated with light, this compound produces small
amounts of what are known as reactive oxygen molecules, that oxidise
surface proteins in the immediate vicinity.

Using a specific enrichment method and mass spectrometry in combination
with statistical data analysis, the scientists can ultimately identify
which molecules have been oxidised.

To determine the distance between the protein of interest and the other molecules, the researchers repeat their experiments under slightly
modified conditions that affect the amount and survival time of the
reactive oxygen molecules. These include the length of irradiation with
light and the choice of medium in which the cells are cultured. The
more reactive oxygen is locally generated and the longer that process continues, the wider the area in which surface molecules get oxidised.



========================================================================== Drugs that are better at targeting cancer Wollscheid and his colleagues
will now use the technology to compare cells from healthy and diseased
people. "We're trying to understand how a disease changes the organisation
of proteins at the cellular level -- for example, when a healthy cell transforms into a cancer cell," Wollscheid says. The scientists are
in the process of creating a reference map of healthy cells. They then
plan to use it to identify differences in the organisation of protein communities on the surface of diseased cells.

Knowing which molecules exist on cell surfaces and how they are organised
could become significant in areas such as the development of novel
drugs to fight cancer. Modern cancer drugs employ a cell-killing agent
is often coupled to an antibody that recognises a surface molecule that
is present in large quantities on cancer cells. This means the cancer
cells are killed with a reasonable degree of specificity. However,
many cancer-specific surface molecules are also found on healthy cells,
albeit at lower concentrations, provoking these drugs to also kill some
healthy cells.

If two molecules were found to be adjacent only on a diseased but not on a healthy cell, drugs could be developed that recognise these two molecules together. The drug would then kill a cell only if both molecules were
present on the cell and adjacent to each other. This is precisely the information that the new technology provides.

A wide range of applications In the published work, the scientists showed
that the scope for using this method goes beyond the investigations
of which cell surface molecules are next to each other. They also
tagged viruses and drugs with the small chemical compound that produces reactive oxygen. This allows the researchers to study the binding events
of viruses or drugs to cells. Furthermore, the method makes it possible
to investigate which protein communities are involved in the interaction between two different cells. The scientists demonstrated this using the
example of communication between immune cells. "In this way, the new
method can help to understand how drugs work and how viruses or immune
cells recognise other cells," says ETH doctoral student Mu"ller. "The
method is therefore of great benefit for research at universities and in industry." Mu"ller and Wollscheid developed and tested the new method
in an interdisciplinary collaboration including ETH Zurich Professors
Martin Loessner, Annette Oxenius, Jeffrey Bode, Erick Carreira and
Berend Snijder.

Researchers from the University of Zurich, the University of Michigan
and an American drug development company also contributed to the study,
which was published in the journal Nature Communications. The scientists
have transferred the new technology to a spin-off company, which now plans
to use the technology to develop new drugs against not only individual
surface proteins but entire protein communities.

========================================================================== Story Source: Materials provided by ETH_Zurich. Original written by
Fabio Bergamin. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Maik Mu"ller, Fabienne Gra"bnitz, Niculo` Barandun, Yang Shen,
Fabian
Wendt, Sebastian N. Steiner, Yannik Severin, Stefan U. Vetterli,
Milon Mondal, James R. Prudent, Raphael Hofmann, Marc van Oostrum,
Roman C.

Sarott, Alexey I. Nesvizhskii, Erick M. Carreira, Jeffrey
W. Bode, Berend Snijder, John A. Robinson, Martin J. Loessner,
Annette Oxenius, Bernd Wollscheid. Light-mediated discovery of
surfaceome nanoscale organization and intercellular receptor
interaction networks. Nature Communications, 2021; 12 (1) DOI:
10.1038/s41467-021-27280-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211202141532.htm

--- up 3 weeks, 2 hours, 55 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)