Evolutionarily Conserved Amino Acid Organization in Protein Low Complexity Regions Encodes Conformation, Dynamics and Assembly

MARTIN, ERIK W.; HOLEHOUSE, ALEX S.; PERAN, IVAN; INCICCO, J. JEREMÍAS; SORANNO, ANDREA; PAPPU, ROHIT V.; MITTAG, TANJA

Congreso; Biophysical society meeting; 2020

Condensation of biomolecules into macroscopic membraneless assemblies is critical to organizing the vast array of complex processes vital to life. A common theme emerging from the ongoing discovery of new types of biomolecular condensates is that they contain an abundance of proteins with intrinsically disordered ?prion-like domains? (PLD). Despite the plethora of diverse interactions that can provide the requisite multivalency that drives the condensation of biomolecules in cells, it is clear that the presence of PLDs in these structures is vitally important. This work links molecular level detail with solution-wide emergent structure giving nuanced insight into the phase separation of PLDs. Combining nuclear magnetic resonance (NMR) spectroscopy, fluorescence microscopy and small-angle X-ray scattering (SAXS) linked by atomistic and coarse-grained simulations, a protocol has emerged to identify adhesive elements in PLDs in molecular level detail and map these features onto the thermodynamics of phase separation. We postulate that idiosyncratic patterns of aromatic amino acids are evolutionarily encoded in PLDs to effectively renormalize these complex biopolymers into pseudo-homopolymers. PLDs with a threshold density of aromatic amino acids evenly, non-randomly, distributed across the sequence will form dynamic, liquid-like, protein dense phases. Sequences that deviate from this patterning can instead lead to aggregation.