Protein condensation

The fields of biology and physics have recently discovered that there are biological proteins that phase separation out of solution to form liquid like protein condensates much the way oil will de-mix from water (see movie 1). So far, this appears to be a very important and general strategy utilized by cells to form compartments with material properties tuned to their specific function. To first approximation, we can understand this process using physical principles developed to understand synthetic polymers. However, unlike synthetic polymers, biological proteins have specific and intricate amino acid sequences. First, this gives rise to an incredibly diverse set of material behaviors which we are only beginning to discover. These include aging similar to glasses (see Movie 2), ultra-low surface tensions, spatially localized wetting, growth into well-ordered fibers as well as active processes. Second, inside of cells, we expect these properties to be quickly tuned by cells through modifications of the protein sequence (eg. phosphorylation).

Movie 1: Protein condensates acting as droplets in the lab

One of the research directions in the lab is to study the material nature of these protein condensates and uncover the physical principles which govern them. Oftentimes our work requires building new tools that can quantitatively measure and manipulate these materials on the lengthscale of microns. We also rely heavily on quantitative image processing. We use this information to build a conceptual framework from which we understand how microscopic processes lead to bulk behaviors. Moreover, we work in close collaboration with theory colleagues to quickly turn this conceptual framework into a rigorous theoretical understanding.

Movie 2: Protein condensates (green) exhibiting liquid like fusion events that slow over time. This indicates the condensates changing their properties from liquid-like (like water) to more solid-like (like a rubber ball). Adapted from Jawerth et al Science 2020.

Fiber formation in condensate forming proteins

Some species of proteins which can form liquid-like condensates, also exhibit growth into fibers (or fibrils), see Movie. One particularly interesting set of such proteins are those that are associated with neurodegeneration in which the fiber growth may be related to the pathological fibrils observed in disease. Although an increasing amount is being discovered about the molecular architecture of these fibers, very little is understood about their higher order architectures as well as the dynamics of their growth. Moreover, they often form in the presence of the droplet-phase of the proteins. This is unusual and unlike other biological fiber formation. The presence of droplets in solution seems to influence the growth of these fibers in interesting ways. There are numerous conjectures about how droplets can alter fiber formation: the presence of droplets could act as reservoirs of monomers leading to increased fiber growth, they could compete for monomers from the solution and slow fiber growth, and the eventual dynamical arrest (glass-like aging) of the droplets may sequester monomers completely. We are using a combination of high resolxution imaging, image processing, atomic force microscopy and other techniques to investigate such behaviors directly.

Fibrils growing in a sea of protein condensates in the lab. Adapted from Boczek et al eLife 2021