Abstract:

Proteins are the workhorse molecules of life. For many proteins, such as enzymes, the protein’s amino acid sequence specifies a stably folded structure that determines function. In contrast, intrinsically disordered proteins (IDPs) are dynamic and do not adopt a stable fold. Modern computational and experimental approaches, such as AlphaFold and cryo-electron microscopy, have enabled major recent advances in understanding sequence-structure-function relationships for folded proteins. However, these approaches have largely failed to explain the molecular language of IDPs and how this language gives rise to function. This is an important knowledge gap to fill, as IDPs have critical roles in health and disease, and engineered IDPs are emerging as novel biomaterials and synthetic biology tools. In this talk, I will share my lab’s research to connect sequence and consequence in several engineered and natural IDPs. I will focus on IDPs that phase separate to form biomolecular condensates, which are membraneless compartments that help organize cellular biochemistry in space and time. I will present two stories illustrating how IDP sequence determines phase behavior and material properties of biomolecular condensates, with potential relevance to neurodegenerative disease. I will conclude by describing how these insights open new directions in engineering condensate-based biotechnologies and therapies.