UC Merced

Intrinsically disordered proteins and protein regions (IDRs) are ubiquitous across all kingdoms of life and are essential to cellular function. Unlike folded proteins, IDRs exist in a collection of rapidly interchanging conformations known as an ensemble. An IDR’s amino acid sequence determines its ensemble, which in turn can play an important role in dictating function. Yet a clear link connecting IDR sequence, its ensemble properties, and its role as sensors of the cellular environment has not been directly established. This dissertation describes a series of projects aimed at understanding how IDRs act as sensors of the cellular environment. Chapter 2 compares in vitro and in-cell experiments of naturally occurring IDRs and establishes that IDR ensembles and sensitivities are recapitulated in live cells. Chapter 3 is unpublished data that builds on the finding that in vitro observations recapitulate in live cells and aims to test IDR sensitivity to different cancer cellular environments, focusing on a larger set of naturally occurring IDRs. This chapter aims to highlight key sequence features that play a role in sensing the cellular environment, specifically different types of cancers. Chapter 4 tests if the same sequence and structural features that enable sensitivity for naturally occurring IDRs holds true for synthetic sequences. This chapter describes a software and validation method to design and test synthetic disordered sequences based on user given parameters. Not only does this allow for an informed high-throughput design of sequences but it also allows scientists to design sequence mutants in a more informed manner. Chapter 5 concludes the dissertation, describes the contributions of the work to the field and suggests directions for further research.