An international group of researchers has put together a groundbreaking map that illustrates how mutations affect the localization of proteins within cells.
To create this map, the team developed a high-throughput imaging system to examine nearly 3,500 mutations and their effects on where proteins are located in the cell. Surprisingly, they discovered that about one in six mutations associated with diseases caused proteins to be mislocated within the cell.
“Thanks to advancements in genetic sequencing, scientists can now identify numerous protein mutations that lead to diseases,” explained Jessica Lacoste, the study’s co-lead author and a postdoctoral fellow at the Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto. “While we can now identify these mutations in patients, we still don’t fully understand how they influence cellular functions. This study aims to fill that gap.”
The findings were recently published in the journal Cell.
Genetic mutations can impact the proteins produced by cells in several ways. For instance, they might weaken the proteins’ overall stability by hindering their ability to fold correctly, alter their interactions with other proteins, or disturb their transportation to various parts of the cell. The first two effects have been researched more extensively, while much less is known about how mutations affect the movement of proteins. Gaining insight into how mutations influence protein localization is crucial for understanding their role in a wide array of human diseases.
To conduct their study, the research team utilized an advanced microscope and applied computational analysis to complement their visual data. They compared the pathways of mutated proteins with those of normal proteins, ultimately discovering that protein mislocalization occurs more frequently than previously believed.
Initially, the researchers thought misplaced proteins were mainly due to disruptions in their interactions with other proteins or by faulty trafficking signals guiding them to their designated locations. They were taken aback to find that the primary reason for mislocalized proteins was the instability of the proteins and their inability to properly integrate into cell membranes.
“We’ve produced the first large-scale map that visualizes the effects of mutations on where proteins are located inside the cell,” remarked Mikko Taipale, a co-principal investigator of the study and a professor of molecular genetics at the Donnelly Centre and U of T’s Temerty Faculty of Medicine. “No one else has researched the impact of pathogenic missense mutations on this scale, tracking how proteins move to various organelles. The mislocalization patterns we’ve identified can clarify the severity of diseases caused by certain mutations, contributing to a better understanding of less studied mutations as well.”
Although the phenomenon of protein mislocalization is not as widely understood compared to the general loss of protein stability or disrupted interactions, it happens just as frequently. For example, the most common mutation associated with cystic fibrosis results in the affected protein being trapped in the endoplasmic reticulum instead of being transported to its correct spot on the cell surface. Current drug therapies that promote proper protein trafficking are being implemented in clinical settings to alleviate this issue and enhance patient symptoms.
“We’ve created a comprehensive database on protein mislocalization, making it accessible for other researchers who wish to deepen our understanding of how genetic variations affect human diseases,” stated Anne Carpenter, co-principal investigator of the study and senior director of the Imaging Platform at the Broad Institute. “One particularly promising application of this data could be to identify treatments that allow mutant proteins to localize correctly, particularly for rare diseases.”
