Protein misfolding plays a role in degenerative diseases, cancer evolution, synthetic biology, bioproducts, and more. Despite its importance in all of these fields, researchers often struggle to understand even the basic mechanisms of protein misfolding. For example, there is no tool to determine how much misfolding is happening inside of any given cell, or which mutations cause severe vs. mild misfolding. Further, there are currently no techniques to measure the degree of misfolding for a given mutant protein with high throughput.
Researchers at the Biodesign Institute of Arizona State University have developed a new technology to allow massively parallel quantification of protein folding and stability, for thousands of mutant proteins at a time. Using this technology, a researcher can choose a protein of interest and study thousands of its mutant variants, comparing their stability as well as their toxicity. This cell-based technology is uniquely designed such that the more a protein of interest misfolds, the faster the cells grow, making interpretation easier. This technology has been validated with yeast cells.
This technology presents a new way to study proteins of interest, analyze variants and quantify their stability and toxicity in order to identify misfolding causing mutants.
Potential Applications
-
Synthetic biology/bioproduction
-
Help design better more efficient strains by showing them which mutations improve protein stability and which harm it
-
-
Diagnostics/screening
-
Help connect an individual's genotype to their risk of developing protein folding disease, or predisposition to more severe disease
-
-
Cancer
-
Build a large database of all the mutations that cause misfolding and use this to predict which tumors are overrun with such mutations and therefore overrun with misfolded proteins
-
Inducing misfolding of key proteins to treat cancer
-
-
Research
-
Understanding mechanisms of protein misfolding
-
Screen many proteins to learn general rules about which types of mutations are damaging to a protein's fold
-
Benefits and Advantages
-
Enables massive parallel quantification of thousands of mutant proteins
-
Quantitative detection
-
The faster the cells grow, the more misfolded the protein is
-
-
Creates comprehensive whole protein maps that show how every amino acid contributes to misfolding as well as toxicity
-
Can determine which mutant causes the most misfolding
-
Allows for measuring relative growth rate
-
Quantifies how toxicity scales with misfolded protein abundance
-
Sensitive enough to detect defects that cause mutant strains to grow only 1% slower than WT, even when applied to pools that exceed 5,000 strains
For more information about the inventor(s) and their research, please see