Medical Research

University of Notre Dame

Patricia Clark, Masaru Kuno
Notre Dame, IN
December 2017

Proteins are central to every cellular mechanism, and proper protein folding is a crucial prerequisite for proper cell function.  Yet established approaches to study protein folding have proven insufficient to develop a predictive understanding of the folding behavior of most proteins, including those implicated in human diseases.  This is due to both our inability to replicate the cellular environment in the test tube and the complexity of studying protein folding in the cell.  In the cell, every protein is synthesized vectorially (from one end to the other) and many proteins fold as they are being synthesized, i.e., vectorially as well.  There is strong – albeit anecdotal – evidence that vectorial folding can significantly alter folding mechanisms, including how likely a protein is to fold correctly rather than misfold and aggregate.  Currently, no method is available to recapitulate vectorial protein folding in the test tube.  As a result, there is no experimental platform available to study in detail its precise effects on folding mechanisms and outcomes.  To overcome these obstacles, two investigators at Notre Dame University will develop a first-of-its-kind approach to explicitly test, with unprecedented detail and on a proteome-wide scale, the impact of vectorial folding on folding mechanism and outcome.  They will use this strategy to study folding mechanisms of proteins that aggregate in typical folding assays.  This approach is expected to transform the current understanding of what leads to proper protein folding, versus aggregation.

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