Giant nanomachine aids the immune system

Date:
August 28, 2020
Source:
Ruhr-University Bochum
Summary:
In order to kill diseased cells, our immune system must first
identify them. The so-called peptide-loading complex plays a key
role in this process. A research team has analyzed this nanomachine
in atomic detail.



FULL STORY ========================================================================== Cells that are infected by a virus or carry a carcinogenic mutation,
for example, produce proteins foreign to the body. Antigenic peptides
resulting from the degradation of these exogenous proteins inside the
cell are loaded by the peptide-loading complex onto so-called major histocompatibility complex molecules (MHC for short) and presented on the
cell surface. There, they are specifically identified by T-killer cells,
which ultimately leads to the elimination of the infected cells. This
is how our immune system defends us against pathogens.


========================================================================== Machine operates with atomic precision The peptide-loading complex
ensures that the MHC molecules are correctly loaded with antigens. "The peptide-loading complex is a biological nanomachine that has to work with atomic precision in order to efficiently protect us against pathogens
that cause disease," says Professor Lars Scha"fer, Head of the Molecular Simulation research group at the Centre for Theoretical Chemistry at RUB.

In previous studies, other teams successfully determined the structure
of the peptide-loading complex using cryo-electron microscopy, but only
with a resolution of about 0.6 to 1.0 nanometres, i.e. not in atomic
detail. Based on these experimental data, Scha"fer's research team in collaboration with Professor Gunnar Schro"der from Forschungszentrum
Ju"lich has now succeeded in creating an atomic structure of the peptide-loading complex.

Exploring structure and dynamics "The experimental structure is
impressive. But only with our computer-based methods were we able to
extract the maximum information content contained in the experimental
data," explains Schro"der. The atomic model enabled the researchers
to perform detailed molecular dynamics computer simulations of the peptide-loading complex and thus to study not only the structure but
also the dynamics of the biological nanomachine.

Since the simulated system is extremely large with its 1.6 million
atoms, the computing time at the Leibnitz Supercomputing Centre in
Munich aided this task considerably. "Using the high-performance
computer, we were able to push into the microsecond time scale in
our simulations. This revealed the role of sugar groups bound to the
protein for the mechanism of peptide loading, which had previously only
been incompletely understood," outlines Dr. Olivier Fisette, postdoc
researcher at the Molecular Simulation research group.

Direct intervention in immune processes The atomic model of the
peptide-loading complex now facilitates further studies. For example,
some viruses try to cheat our immune system by selectively switching off certain elements of the peptide-loading complex. "One feasible objective
we'd like to pursue is the targeted intervention in these processes,"
concludes Scha"fer.


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


========================================================================== Journal Reference:
1. Olivier Fisette, Gunnar F. Schro"der, Lars V. Scha"fer. Atomistic
structure and dynamics of the human MHC-I peptide-loading complex.

Proceedings of the National Academy of Sciences, 2020; 117 (34):
20597 DOI: 10.1073/pnas.2004445117 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200828091953.htm

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