Large molecules need more help to travel through a nuclear pore into the
cell nucleus

Date:
August 24, 2020
Source:
Johannes Gutenberg Universitaet Mainz
Summary:
Model systems based on virus capsids have shown how large
biomolecules are able to penetrate a cell nucleus. The larger the
molecule, the more nuclear localization signals are needed.



FULL STORY ==========================================================================
A new study in the field of biophysics has revealed how large molecules
are able to enter the nucleus of a cell. A team led by Professor Edward
Lemke of Johannes Gutenberg University Mainz (JGU) has thus provided
important insights into how some viruses, for example, can penetrate
into the nucleus of a cell, where they can continue to proliferate
and infect others. They have also demonstrated that the efficiency of
transport into a cell decreases as the size of the molecules increases
and how corresponding signals on the surface can compensate for this.


==========================================================================
"We have been able to gain new understanding of the transport of large biostructures, which helped us develop a simple model that describes
how this works," said Lemke, a specialist in the field of biophysical chemistry. He is Professor of Synthetic Biophysics at JGU and Adjunct
Director of the Institute of Molecular Biology (IMB) in Mainz.

Nuclear localization signals facilitate rapid entry A typical mammalian
cell has about 2,000 nuclear pores, which act as passageways from the
cell cytoplasm into the cell nucleus and vice versa. These pores in the
nuclear envelope act as gatekeepers that control access and deny entry
to larger molecules of around five nanometers in diameter and greater.

Molecules that have certain nuclear localization sequences on their
surface can bind to structures within nuclear pores, allowing them
to enter into the nucleus rapidly. "Nuclear pores are remarkable in
the diversity of cargoes they can transport. They import proteins and
viruses into the nucleus and export ribonucleic acids and proteins into
the cell cytoplasm," explained Lemke, describing the function of these
pores. "Despite the fundamental biological relevance of the process, it
has always been an enigma how large cargoes greater than 15 nanometers
are efficiently transported, particularly in view of the dimensions
and structures of nuclear pores themselves." With this is mind and as
part of their project, the researchers designed a set of large model
transport cargoes. These were based on capsids, i.e., protein "shells"
in viruses that enclose the viral genome. The cargo models ranging
from 17 to 36 nanometers in diameter were then fluorescently labeled,
allowing them to be observed on their way through cells. Capsid models
without nuclear localization signals on their surface remained in the cell cytoplasm and did not enter the cell nucleus. As the number of nuclear localization signals increased, the accumulation of the model capsid
in the nucleus became more efficient. But even more interestingly, the researchers found that the larger the capsid, the greater was the number
of nuclear localization signals needed to enable efficient transport
into the nucleus.

The research team looked at a range of capsids of various viruses
including the hepatitis B capsid, the largest cargo used in this
study. But even increasing the number of nuclear localization signals to
240 did not result in the transport of this capsid into the nucleus. This corresponds with the results of earlier studies of the hepatitis B virus
that have indicated that only the mature infectious virus is capable of
passage through a nuclear pore into the nucleus.

Cooperation enabled the development of a mathematical model In cooperation
with Professor Anton Zilman of the University of Toronto in Canada,
a mathematical model was developed to shed light on the transport
mechanism and to establish the main factors determining the efficiency of transport. "Our simple two-parameter biophysical model has recreated the requirements for nuclear transport and revealed key molecular determinants
of the transport of large biological cargoes on cells," concluded first
author Giulia Paci, who carried out the study as part of her PhD thesis
at the European Molecular Biology Laboratory (EMBL) in Heidelberg.


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


========================================================================== Journal Reference:
1. Giulia Paci, Tiantian Zheng, Joana Caria, Anton Zilman, Edward
A Lemke.

Molecular determinants of large cargo transport into the
nucleus. eLife, 2020; 9 DOI: 10.7554/eLife.55963 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200824120048.htm

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