We study how function is encoded BY disordered protein REGIONS

We do this in the Department of Biochemistry and Molecular Biophysics at Washington University School of Medicine using a combination of physics-based simulations, computational biology, and experimental approaches.

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 a wide variety of cellular functions. 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.

Scientific 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, many 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 focused 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

LAB ETHOS

A major goal of our group is to create an environment that is safe and supportive for lab members from all communities and backgrounds. Diversity in experience, perspective, and culture is a major asset and one that can only be realized through an inclusive environment that promotes and supports the success of scientists from groups that are traditionally underrepresented in science, technology, engineering, and mathematics (STEM). This support extends beyond our physical lab space to all members of the broader scientific community, and trainees from groups underrepresented in STEM should feel welcome to contact Alex or another member of the lab for support and advice.

Funding Acknowledgement

The Holehouse lab has been lucky enough to receive generous support from several funding sources. We gratefully acknowledge these sources, and in particular, the American tax payer.

Active funding

NIH (Office the Director, NCI administered) (2023 – 2028) [DP2-CA290639]
Project title: Uncovering the regulatory logic of gene expression encoded by disordered regions
Role: Principal Investigator
Link: NIH RePORTER

HFSP (2022 – 2025) [RGP0015/2022]
Project title: Molecular Determinants of Evolutionary Conservation in Disordered Protein Regions
Role: Principal Investigator (with Hyun Kate Lee and Dolf Weijers)

NSF (DBI) (2022 – 2027) [2213983]
Project title: BII: Life Without Water: Protecting Macromolecules, Cells, and Organisms During Desiccation and Rehydration Across Kingdoms of Life
Role: Co-Principal Investigator
Link: NSF website, WALII website

NSF (MCB) (2021 – 2025) [2128068]
Project title: IntBIO: Collaborative Research: Functional Synergy Between Disordered Proteins and their Environment in Desiccation Protection
Role: Principal Investigator (with Shahar Sukenik and Thomas Boothby)
Link: NSF website

NIH (NIAID) (2022 – 2027) [R01AI163142]
Project title: A Multipronged Investigation of SARS-CoV-2 Genome Packaging (with Andrea Soranno and Kathleen Hall)
Role: Co-Investigator
Link: NIH RePORTER

NIH (NIGMS) (2021 - 2025) [R01GM142164]
Project title: Intrinsic Disorder and Agonist Bias in EGF Receptor Signaling (with Linda Pike)
Role: Co-Investigator
Link: NIH RePORTER

Longer Life Foundation (2020 – 2023)
Project title: Predicting the Functional Impact of Genetic Variation Within Intrinsically Disordered Protein Regions
Role: Principal Investigator

Expired funding

Dewpoint Therapeutics Sponsored Research Agreement (2020-2022)