Characteristics and Emergent Behaviors of Multisite Intrinsically Disordered Proteins
- Author(s): Clemens, Lara
- Advisor(s): Allard, Jun
- et al.
Proteins perform diverse jobs around the cell, including transporting nutrients and transmitting signals across membranes. For a long time, the traditional understanding of proteins has been that a protein's structure determines its function. However, recent research shows that more than 40% of human proteins contain intrinsically disordered domains, or pieces of protein lacking a stable structure. These domains have been found in diverse biological systems, including associated with the cytoskeleton, immune receptor tails, and as linkers between structured domains. Given their abundance and variety, it has become critical to understand how disordered domains behave. Here we investigate how characteristics of disordered proteins --- including length, binding site location, long- and short- lived interactions with other domains --- influence their binding kinetics. Specifically, we consider three disordered proteins in different biological systems: (1) multiply phosphorylated T cell receptor cytoplasmic tails, (2) formins --- a family of actin polymerization mediators, and (3) PD-1 tethered T cell signaling inhibition. For the T cell receptor cytoplasmic tails and formins, we use a freely-jointed chain model to simulate interactions between multisite disordered domains (e.g. T Cell Receptor, formin) and a binding partner (e.g. kinase, profilin-actin) represented as an idealized spherical domain. In each case, we demonstrate that disorder naturally leads to site-specific binding rates in multisite domains. For T cell receptor tails, we also demonstrate how physical changes due to post-translational modifications can give rise to positive cooperativity, negative cooperativity, and ultrasensitivity. We next show how variation between formin homologues, such as dimerization state, length, and binding site locations, can lead to changes in actin polymerization rate. Lastly, we analyze surface plasmon resonance experiments of the phosphatase SHP-1 dephosphorylating its tether, PD-1. We couple worm-like chain models with differential equations to extract binding kinetics, catalytic rates, and molecular reach parameters from the data. We use this data to quantify how changes in the lengths of disordered domains influence the rate and reach of reactions. Together, these results demonstrate the diversity and complexity of roles disordered proteins can play in cellular processes.