Mutations linked to neurological disease enhance self-association of low-complexity protein sequences

Protein domains of low sequence complexity do not fold into stable, three-dimensional structures. Nevertheless, proteins with these sequences assist in many aspects of cell organization, including assembly of nuclear and cytoplasmic structures not surrounded by membranes. The dynamic nature of these cellular assemblies is caused by the ability of low-complexity domains (LCDs) to transiently self-associate through labile, cross-b structures. Mechanistic studies useful for the study of LCD self-association have evolved over the past decade in the form of simple assays of phase separation. Here, we have used such assays to demonstrate that the interactions responsible for LCD self-association can be dictated by labile protein structures poised close to equilibrium between the folded and unfolded states. Furthermore, missense mutations causing Charcot-Marie-Tooth disease, frontotemporal dementia, and Alzheimer's disease manifest their pathophysiology in vitro and in cultured cell systems by enhancing the stability of otherwise labile molecular structures formed upon LCD self-association.

Automated summary

Protein domains of low sequence complexity do not form stable, three-dimensional structures. However, they play a role in assisting cell organization by self-associating through labile structures. Studies have shown that the interactions responsible for this self-association can be influenced by the equilibrium between folded and unfolded states of the protein structures. Furthermore, certain missense mutations enhance the stability of the labile structures formed during LCD self-association, leading to the manifestation of diseases.