By stopping cells with mutated or damaged DNA from dividing, the p53 protein helps prevent the development of tumors. However, the protein breaks down rapidly in the cell. Researchers at Karolinska Institute (KI) in Sweden have now found a way of stabilizing the protein by adding a spider silk protein. Their findings show 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 in a paper titled, “A ‘spindle and thread’-mechanism unblocks p53 translation by modulating N-terminal disorder.”
“Disordered proteins pose a major challenge to structural biology. A prominent example is the tumor suppressor p53, whose low expression levels and poor conformational stability hamper the development of cancer therapeutics,” the researchers wrote. “All these characteristics make it a prime example of ‘life on the edge of solubility.’ Here, we investigate whether these features can be modulated by fusing the protein to a highly soluble spider silk domain (NT∗).”
“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,” said the study’s last author Michael Landreh, researcher at the department of microbiology, tumor and cell biology, Karolinska Institute. “We’ve been inspired by how nature creates stable proteins and have used spider silk protein to stabilize p53. Spider silk consists of long chains of highly stable proteins, and is one of nature’s strongest polymers.”
In a collaborative project with, among 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.
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.
“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,” said co-author and senior professor Sir David Lane at Karolinska Institute. “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.”
Lane was one of the discoverers of the p53 protein in the late 1970s.
“In summary, we demonstrate that inducing co-translational folding via a molecular ‘spindle and thread’ mechanism unblocks protein translation in vitro,” concluded the researchers.