EDITOR’S CHOICE IN CANCER
Typically, healthy cells produce small amounts of a protein called p53, which triggers apoptosis and helps prevent cancer. But p53’s length and flexibility make it unstable and prone to getting stuck in ribosomes during translation. That makes creating stable forms of the protein a common goal for cancer researchers interested in developing p53-based therapies, says Karolinska Institutet microbiologist and physical chemist Michael Landreh.
Landreh’s group was working with p53 and, separately, with a class of proteins called major ampullate spidroins, which help solidify dragline spider silk, when the researchers tried combining the two. The team used gene editing techniques to combine the gene for p53 with a sequence encoding the spider silk protein’s lengthy N-terminal domain and inserted the product into a bacterial plasmid. Landreh confesses that he didn’t think fusing the two would accomplish much, but he was pleasantly surprised with the result: human cells produced the hybrid protein 10 times more efficiently than they did p53, and the hybrid was considerably more stable. In subsequent experiments, he adds, the protein was also more efficient at killing lab-grown tumors. During translation, the spider silk portion physically pulls the p53 protein through the ribosome, serving as a core around which p53’s floppy segment wraps itself, forming what Landreh calls “a stable, compact version.” He notes that the technique is “far from killing real cancer cells, but that’s something we want to do.”
“This paper is based on a very interesting idea,” says University of Manitoba molecular biologist Ayesha Saleem, who didn’t work on the study, adding that “the authors did a great job of providing proof of concept that fusing p53 protein with the N-terminal domain of spider silk protein . . . improved the stability of p53 without affecting its biological function.”
M. Kaldmäe et al., “A ‘spindle and thread’ mechanism unblocks p53 translation by modulating N-terminal disorder,” Structure, 30: 733–42, 2022.
This article was featured in July 2022, Issue 1 of the digest