Genetic Tool Monitors and Manipulates Cellular Protein Aggregates

By LabMedica International staff writers
Posted on 31 Oct 2017

A newly developed genetic tool allows researchers to track the level of protein aggregation in cells, and to a certain extent, manipulate or eliminate the aggregates.

Protein aggregation is a hallmark of many diseases but also underlies a wide range of positive cellular functions. This phenomenon has been difficult to study because of a lack of quantitative and high-throughput cellular tools.

Image: The yTRAP can be used to create cellular sensors for protein aggregation. The sensor produces fluorescent signals that depend on the protein aggregation state in the cell. In this experiment, three cell types were tested that produce varying signal strength depending on the aggregation of a prion protein. The brightest green for no prion aggregation (bottom), a slightly dimmer green to show a weak presence of prion aggregation (top right) and an even dimmer green signal for a strong prion presence (top left) (Photo courtesy of Dr. Ahmad S. Khalil).

To correct this lack, investigators at the Boston University College of Engineering (MA, USA) developed a synthetic genetic tool to sense and control protein aggregation. This tool - called yTRAP for yeast Transcriptional Reporting of Aggregating Proteins - was composed of two parts: one segment attached to the protein of interest and the other produced a fluorescent signal to measure the amount of aggregation in the cell.

The investigators worked with a yeast model system. They ported in the October 19, 2017, online edition of the journal Cell that by utilizing high-throughput screens, they were able to identify prion-curing mutants and engineer “anti-prion drives” that reversed the non-Mendelian inheritance pattern of prions and eliminated them from yeast populations. They extended ther technology to yeast RNA-binding proteins (RBPs) by tracking their propensity to aggregate, searching for co-occurring aggregates, and uncovering a group of coalescing RBPs through screens enabled by the platform.

This work established a quantitative, high-throughput, and generalized technology to study and control diverse protein aggregation processes in cells.

"Protein aggregates can cause a cell to gain or lose a function," said senior author Dr. Ahmad S. Khalil, assistant professor of biomedical engineering at Boston University College of Engineering. "It could be beneficial or harmful. For example, it could allow a cell to survive stressful conditions or change its metabolic function to digest a different type of sugar. And the discovery of these beneficial functions has often been serendipitous."

Related Links:
Boston University College of Engineering