Imagine turning water into ice by heating it. Some proteins in our bodies manage similar shifts from soluble to insoluble in response to changes in temperature and other environmental cues. Now, scientists report that they have deciphered a set of rules that govern when these shifts occur, and they have used those rules to program proteins to change their solubility on demand. Such temperature-triggered transitions might eventually offer researchers new ways to deliver medicines in the body.
Proteins are master shapeshifters. All start out as linear chains of simple chemical compounds called amino acids, which then fold up into 3D shapes that carry out the protein’s specific function. But some proteins are more prone to shapeshifting than others. A muscle fiber protein called elastin, for example, assembles and disassembles depending on shifting temperature: Inside the cell the protein is soluble, but outside, where interactions with other molecules effectively make it warmer, it becomes insoluble. Elastin’s transitions give muscles an elastic quality, allowing them to stretch, contract, and then regain their original shape.
Specific amino acid sequences in the proteins control these changes, but scientists weren’t sure they had identified all of them. “We went on this sort of quest to find [additional] sequences,” says study co-author Ashutosh Chilkoti, a biomedical engineer at Duke University in Durham, North Carolina.
Chilkoti and Felipe Quiroz, a cell biologist at Rockefeller University in New York City, started building a library of elastinlike proteins, basing the sequences off of five key amino acids found in elastin. To test their synthetic designs, the team engineered E. coli to grow proteins with these sequences, isolated them, and watched to see whether they would shift from soluble to insoluble on cue. Based on the results, they devised a set of rules governing which sequences were most likely to induce shapeshifts, as they report today in Nature Materials. Though the rules didn’t work every time, Chilkoti says the guidelines give researchers a new way to tailor the way engineered proteins behave in the body.
The new work is valuable because, for the first time, it tells researchers the precise amino acid sequences they need to control protein shapeshifting, says Rohit Pappu, a biological systems engineer at Washington University in St. Louis, Missouri, who was not affiliated with the study. “That’s essentially where I think this work has the prospect of going.”
The Duke researchers hope that with their table of rules, they will eventually be able to use synthetic proteins as a drug delivery vehicle. One possibility, Chilkoti says, is to design synthetic proteins that mix uniformly with drugs at room temperature, but then turn insoluble at body temperature. When injected, the proteins would glom onto each other and trap the drugs in a sort of gellike capsule. Over time, the medicine would leak out, leaving a protein glob that natural degradation processes in the body break down and flush out. Such designer drug delivery vehicles don’t exist yet. But Pappu says the new shapeshifting rules make them worth pursuing. “We might actually have a prayer of true designer materials.”