Spider silk can stabilize cancer-suppressing protein
Date:
March 14, 2022
Source:
Karolinska Institutet
Summary:
The p53 protein protects our cells from cancer and is an interesting
target for cancer treatments. The problem is, however, that it
breaks down rapidly in the cell. Researchers have now found an
unusual way of stabilizing the protein and making it more potent. By
adding a spider silk protein to p53, they show that it is possible
to create a protein that is more stable and capable of killing
cancer cells.
FULL STORY ==========================================================================
The p53 protein protects our cells from cancer and is an interesting
target for cancer treatments. The problem is, however, that it breaks down rapidly in the cell. Researchers at Karolinska Institutet in Sweden have
now found an unusual way of stabilising the protein and making it more
potent. By adding a spider silk protein to p53, they show that it is
possible to create a protein that is more stable and capable of killing
cancer cells. The study is published in the journal Structure.
==========================================================================
P53 plays a key role in the body's defence against cancer, in part by discovering and preventing genetic mutations that can lead to cancer. If
a cell is lacking functional p53, it quickly becomes a cancer cell
that starts to divide uncontrollably. Researchers around the world are therefore trying to develop cancer treatments that in some way target p53.
"The problem is that cells only make small amounts of p53 and then
quickly break it down as it is a very large and disordered protein," says
the study's last author Michael Landreh, researcher at the Department
of Microbiology, Tumor and Cell Biology, Karolinska Institutet. "We've
been inspired by how nature creates stable proteins and have used spider
silk protein to stabilise p53. Spider silk consists of long chains of
highly stable proteins, and is one of nature's strongest polymers."
In a collaborative project with, amongst others, Jan Johansson and Anna
Rising at KI's Department of Biosciences and Nutrition, who use spider
silk in their research, the researchers attached a small section of a
synthetic spider silk protein onto the human p53 protein. When they then introduced it into cells, they found that the cells started to produce
it in large quantities. The new protein also proved to be more stable
than ordinary p53 and capable of killing cancer cells. Using electron microscopy, computer simulations, and mass spectrometry, they were able
to show that the likely reason for this was the way the spider silk part managed to give structure to p53's disordered sections.
The researchers now plan to study the protein's structure in detail and
how its different parts interact to prevent cancer. They also hope to
find out how the cells are affected by the new potent p53 protein and
how well they tolerate its spider-silk component.
"Creating a more stable variant of p53 in cells is a promising approach to cancer therapy, and now we have a tool for this that's worth exploring,"
says co-author and senior professor Sir David Lane at Karolinska
Institutet. "We eventually hope to develop an mRNA-based cancer vaccine,
but before we do so we need to know how the protein is handled in the
cells and if large amounts of it can be toxic." Sir David Lane was one
of the discoverers of the p53 protein in the late 1970s.
P53 has been called the guardian of the genome since it can stop cells
with DNA damage turning into cancer cells. Mutations of the p53 gene
are found in roughly half of all cancer tumours, which makes it the most
common genetic change in cancer.
The study was a collaboration between researchers at Karolinska
Institutet, KTH Royal Institute of Technology and Stockholm University
in Sweden and A*STAR (Agency for Science, Technology and Research) in Singapore. It was supported by grants from several bodies, including
the Swedish Foundation for Strategic Research, Karolinska Institutet,
the Swedish Cancer Society, the Swedish Research Council, Vinnova,
the Olle Engkvist Foundation, the Swedish Society for Medical Research
(SSMF), Formas and the AAke Wiberg Foundation. The authors report no
conflicts of interest.
========================================================================== Story Source: Materials provided by Karolinska_Institutet. Note: Content
may be edited for style and length.
========================================================================== Journal Reference:
1. Margit Kaldma"e, Thibault Vosselman, Xueying Zhong, Dilraj Lama,
Gefei
Chen, Mihkel Saluri, Nina Kronqvist, Jia Wei Siau, Aik Seng Ng,
Farid J.
Ghadessy, Pierre Sabatier, Borivoj Vojtesek, Me'doune Sarr, Cagla
Sahin, Nicklas O"sterlund, Leopold L. Ilag, Venla A. Va"a"na"nen,
Saikiran Sedimbi, Marie Arsenian-Henriksson, Roman A. Zubarev,
Lennart Nilsson, Philip J.B. Koeck, Anna Rising, Axel Abelein,
Nicolas Fritz, Jan Johansson, David P. Lane, Michael Landreh. A
"spindle and thread" mechanism unblocks p53 translation by
modulating N-terminal disorder.
Structure, 2022; DOI: 10.1016/j.str.2022.02.013 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220314120705.htm
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