Structural Basis for the Phase Separation of the Chromosome Passenger Complex

Abstract

Membraneless intracellular compartmentalization is central to a long and growing list of biochemical transactions at diverse sub-cellular locations 1. Proteins are by-and-large the drivers of the formation of these compartments, but there is debate about whether their underpinnings are either low-affinity/low-specificity interactions yielding phase separation 2 or multivalent site-specific interactions 3. By its very nature, ascertaining the former type of interaction is essentially intractable by conventional structural biology methodologies. Moreover, the latter type of interaction is typically beyond current structural approaches, since multivalency involving contacts with highly flexible surfaces confounds traditional methodologies used in structural studies. Approaches that provide mechanistic insight on specific complexes engaged in membraneless compartmentalization are highly limited to date, especially when the molecules undergoing putative phase separation are more complex than a relatively small individual polypeptide. There is some reported success with crosslinking approaches 4 and NMR 5–7 but deciphering the physical basis of membraneless compartmentalization will ultimately require advancing new technologies and/or new applications of existing ones. The proposed types of bonds that are involved in phase separation are similar to those involved in conventional protein folding and interactions (e.g. hydrophobic and electrostatic interactions) 1; however, specifically how the structure and dynamics of a protein or protein complexes are impacted upon engaging in higher-order interactions is almost entirely unknown.