Misfolded Protein Structure

The same protein can adopt many different misfolded structures, each of which can be associated with a different disease.  However, we do not know the full repertoire of misfolded structures that a single protein can adopt, nor do we understand which are associated with specific pathologies.  Our lab is developing new biochemical approaches to reveal misfolded protein structure in living cells.

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The structure of a misfolded protein is a critical determinant of its pathology.  For example, different misfolded states of the same protein can have dramatically different effects on cells and can even be associated with different diseases.  Unfortunately, because misfolded proteins tend to be dynamic and heterogeneous, it is difficult to determine what distinguishes misfolded states with different pathologies.  Moreover, because many different misfolded states can coexist, it is difficult to determine which is responsible for a particular feature of pathology.  We recently pioneered the use of deep mutational scanning, in which large libraries of protein missense variants are screened for relative activity, to identify conformational states of proteins responsible for cellular pathology.  The comprehensive data afforded by this approach allows us to build high-resolution models for culprit species.  We are currently developing related methods that will allow us to study misfolded proteins isolated from disease models or even patients, which we hope will reveal the full repertoire of toxic protein species.  We are also extending our methods to study the structure of proteins in their native cellular environments, which will allow us to determine the structural basis for a variety of remarkable yet enigmatic biochemical phenomena.