We study how function is encoded into disordered proteins

The Holehouse lab will open in January 2020 in the Department of Biochemistry and Molecular Biophysics at Washington University School of Medicine.

TL/DR: A large fraction of proteins and protein-regions are classified as ‘intrinsically disordered’. These regions have historically been hard to study, but play key roles in wide variety of cellular function. Furthermore, these regions are strongly implicated in many diseases. In the Holehouse lab, we integrate a range of computational approaches (simulations, bioinformatics, systems biology) with experimental data to uncover how intrinsically disordered regions mediate cellular function, with a particular interest in biological phase separation.

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Overview

We often think of proteins as tiny well-defined machines that mediate biological function in a way that is inherently linked to their 3D structure. However, a large fraction of protein regions are referred to as ‘intrinsically disordered’ - regions that don’t fold into a well-defined 3D shape, but instead exist in an ensemble of conformations.

These intrinsically disordered regions (IDRs) play key roles in a wide variety of cellular functions, including gene expression, signal transduction, and the stress response. They are also frequently mutated in diseases, from neurodegenerative conditions to cancer. Despite their cellular importance and clinical significance, we lack effective generalizable ways to predict and understand function from sequence.

Our lab is focussed on combining bioinformatics with statistical physics and quantitative cell biology to uncover the general principles that underlie how function is encoded into disordered proteins. We do this by performing simulations and/or sequence-based analysis, and then testing predictions that come from these computational approaches experimentally. Of particular interest is how IDRs can act in a regulatory capacity, how and why IDRs evolve, and how intracellular phase transitions contribute to cellular fitness and function