Disorder, promiscuity, and toxic partnerships

Abstract

Many genes are toxic when overexpressed, but general mechanisms for this toxicity have proven elusive. Vavouri et al. (2009) find that intrinsic protein disorder and promiscuous molecular interactions are strong determinants of dosage sensitivity, explaining in part the toxicity of dosage-sensitive oncogenes in mice and humans.

Figure 1. Too much gene expression is not the same as too little

(A) Genes that lead to cell death or growth defects upon knockout or knockdown tend to preferentially associate with each other in the same protein complexes, shown here by representing proteins as circles and protein-protein associations by lines forming a network of protein interactions. Complexes of essential proteins tend to contain more protein constituents than nonessential complexes. These trends explain a large fraction (>30%) of the essential genes in yeast cells (Hart et al., 2007; Wang et al., 2009). (B) In contrast to genes that are essential upon knockout or knockdown, a different mechanism appears to underlie the toxicity observed upon gene overexpression (Vavouri et al., 2009). Such dosage sensitive genes tend to participate in larger numbers of direct pairwise protein interactions, shown here with dosage sensitive genes forming hubs in a network of yeast two-hybrid protein interactions. Dosage sensitive genes also tend to be intrinsically disordered, as illustrated by the dashed line for the protein structure pictured in the inset. Overexpression of an intrinsically disordered protein may increase its already high degree of interaction promiscuity, leading to toxic partnerships and detrimental effects on the cell.