In cells, there is a careful coordination of activity among molecules. Genes have to be expressed in the right cells at the right times, and the proteins that genes encode for must be properly folded into specific three-dimensional shapes so they will work properly. Proteins also usually have to go to the right places in cells to properly perform their function. Scientists have now learned more about how genetic mutations can cause proteins to end up in the wrong places, or mislocalize. This study has shown that about one in every six genetic mutations that is linked to disease causes a protein to end up in the wrong place in a cell. The findings have been reported in Cell.
Technological advances in genetic sequencing have allowed researchers to identify thousands of protein mutations that cause disease, noted first study author Jessica Lacoste, PhD, a postdoctoral researcher at the University of Toronto (U of T). "We are now able to identify these mutations in patients at the clinic, but we have no idea what their consequences are for cellular processes. This study was meant to help bridge that gap in knowledge."
Genetic mutations can lead to dysfunctional proteins in various ways; they might cause the protein's amino acid sequence to be too short, or too long, for example; or they may lead to problems with the three-dimensional structure of the protein. But genetic mutations can also cause proteins to mislocalize. In recent decades, scientists have learned more about mutations that impair protein structure or function, and less about those that cause mislocalization.
In this work, the researchers utilized powerful microscopy and computational tools to determine where mutated proteins ended up in the cell compared to their normal counterparts. Mislocalization was found to be more common that we have known. The primary cause of mislocalization seems to be impairments in a protein's ability to integrate into a membrane, and is not usually due to problems with protein interactions or stability.
"No one else has studied the impact of pathogenic missense mutations on a scale like this, where we've tracked the movement of proteins to different organelles," noted co-corresponding study author Mikko Taipale, a professor at U of T, among other appointments. "The patterns of mislocalization we've observed help explain disease severity caused by certain mutations and improve our understanding of mutations that were less studied."
For example, a common mutation associated with cystic fibrosis causes the mutant protein to go to an organelle called the endoplasmic reticulum, instead of the cell surface as it normally should.
There are some therapeutics that aim to restore proteins to their correct location and address the issues caused by mislocalization. But more focus on this issue appears to be needed.
"We've made our protein mislocalization database available as a comprehensive resource that can be used by other researchers to expand our collective knowledge on the effects of genetic variation on human disease," said co-corresponding study author Anne Carpenter, senior director of the Imaging Platform at the Broad Institute. "One particularly useful application of this data would be to identify compounds that could help mutant proteins localize correctly to treat rare diseases."
Sources: University of Toronto, Cell