Negative noodles, and positive ones too: Biophysics and bioengineering of intrinsically disordered proteins
Intrinsically disordered proteins (IDPs) do not fold into a fixed three-dimensional structure, yet they play important roles in biology. For instance, many IDPs phase separate into biomolecular condensates that function as membrane-less organelles in cells. If IDPs are somewhat like a cooked noodle, then condensates are roughly akin to a ball of cooked spaghetti, or perhaps pasta primavera. In this talk, I will describe three recent studies from my lab and collaborators, relating to the biophysics and bioengineering of these “noodles.” I will begin by discussing engineered IDPs (including highly charged sequences) that have provided new insights into the molecular grammar of protein phase separation. Second, I will present biophysical insights into the role of protein condensation in the SARS-CoV-2 viral lifecycle, focusing on how phosphorylation within a cationic disordered
region toggles the material state and function of nucleocapsid protein condensates. Third, I will demonstrate how nanoparticle surface engineering allowed us to achieve controlled and orthogonal partitioning of large particles into IDP condensates. Together, these vignettes help link IDP sequence, phase behavior, rheology, and function, with implications for condensate biology and therapeutic targeting of condensates in disease.