Alex Holehouse, Ph.D.

Assistant Professor
Biochemistry and Molecular Biophysics

Biochemistry, Biophysics, and Structural Biology Program
Computational and Systems Biology Program
Molecular Cell Biology Program

  • 223B McDonnell Sciences

  • alex.holehouse@wustl.edu

  • https://www.holehouselab.com/

  • Understand how function is encoded into disordered sequences using a combination of computational and experimental approaches

Research Abstract:

Intrinsically disordered proteins (IDPs) and regions (IDRs) make up around one third of all eukaryotic proteomes and are found in a wide range of proteins critical for cellular function. Despite their abundance, we lack a general understanding of how function is encoded into IDPs. This is in contrast to folded domains, where decades of work have led to powerful bioinformatics tools that are able to identify specific functionally-annotated domains directly from sequence.

Our goal is to understand how function is encoded into disordered sequences using a combination of computational and experimental approaches. Rather than treating IDRs as protein dark-matter, we wish to understand - at a mechanistic level - how IDRs mediate function. By developing general approaches we will be able to uncover new mechanistic insight, explore how IDRs vary across evolution, and predict new protein function from sequence alone.

From a clinical perspective, mutations in IDRs are substantially over-represented in many diseases, including neurodegenerative conditions, rare genetic disorders, and many types of cancer. By approaching our problems through a mechanistic lens, we hope to provide insight into the molecular etiology of these diseases, ultimately opening new avenues for treatment.

We combine computational and experimental approaches to explore the relationship between sequence and function in IDRs. Specifically, we use all-atom and coarse-grained simulations coupled with a range of bioinformatics approaches and quantitative cell biology. A major focus of the lab is on the development of robust computational tools using industry standard practices. With a range of methods at our disposal, we can integrate many different types of data to better understand complex biological systems in a quantitative, mechanistic, and predictive way.

Mentorship and Commitment to Diversity Statement:
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.

Selected Publications:

Select publications from 2021

Holehouse, A. S.†, Ginell, G. M., Griffith, D., & Böke, E†. (2021). Clustering of aromatic residues in prion-like domains can tune the formation, state, and organization of biomolecular condensates. Biochemistry, In Press

Cubuk, J., Alston, J. J., Incicco, J. J., Singh, S., Stuchell-Brereton, M. D., Ward, M. D., Zimmerman, M. I., Vithani, N., Griffith, D., Wagoner, J. A., Bowman, G. R., Hall, K. B., Soranno, A.†, & Holehouse, A. S†. (2021). The SARS-CoV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA. Nature Communications, 12(1), 1936.

Griffith, D., & Holehouse, A. S. (2021). PARROT is a flexible recurrent neural network framework for analysis of large protein datasets. eLife, 10.

Emenecker, R. J., Griffith, D., & Holehouse, A. S. (2021). Metapredict: a fast, accurate, and easy-to-use predictor of consensus disorder and structure. Biophysical Journal. https://doi.org/10.1016/j.bpj.2021.08.039

Taneja, I., & Holehouse, A. S. (2021). Folded domain charge properties influence the conformational behavior of disordered tails. Current Research in Structural Biology, 3, 216–228.

Alston, J. J., Soranno, A., & Holehouse, A. S. (2021). Integrating single-molecule spectroscopy and simulations for the study of intrinsically disordered proteins. Methods , 193, 116–135.

Hesgrove, C. S., Nguyen, K. H., Biswas, S., Childs, C. A., Shraddha, K. C., Medina, B. X., Alvarado, V., Sukenik, S., Yu, F., Malferrari, M., Francia, F., Venturoli, G., Martin, E. W., Holehouse, A. S., & Boothby, T. C. (2021). Molecular Swiss Army Knives: Tardigrade CAHS Proteins Mediate Desiccation Tolerance Through Multiple Mechanisms. In bioRxiv (p. 2021.08.16.456555). https://doi.org/10.1101/2021.08.16.456555

Sankaranarayanan, M., Emenecker, R. J., Jahnel, M., Trussina, I. R. E., Wayland, M., Alberti, S., Holehouse, A. S., & Weil, T. T. (2021). The arrested state of processing bodies supports mRNA regulation in early development. Developmental Cell, In Press

Dorone, Y., Boeynaems, S., Flores, E., Jin, B., Hateley, S., Bossi, F., Lazarus, E., Pennington, J. G., Michiels, E., De Decker, M., Vints, K., Baatsen, P., Bassel, G. W., Otegui, M. S., Holehouse, A. S., Exposito-Alonso, M., Sukenik, S., Gitler, A. D., & Rhee, S. Y. (2021). A prion-like protein regulator of seed germination undergoes hydration-dependent phase separation. Cell, 184(16), 4284–4298.e27.

Last Updated: 10/4/2021 7:25:07 PM

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