Protein intrinsic disorder: a double-edged sword?

Intrinsically disordered proteins and regions (IDPs/IDRs) adopt highly heterogeneous and dynamic conformational states. They perform important regulatory and signaling roles and were shown to engage in weak interactions with other proteins, some of which however, might be non-functional. One may therefore wonder how evolution has limited the non-functional interactions that IDRs would form in the cell. According to the law of mass action, non-functional interactions should increase with the protein abundance level. We hence investigated how various intrinsic properties of S. cerevisiae proteins, particularly those of IDRs, vary with protein abundance and studied the patterns of physical and functional interactions they form in high confidence protein-protein interaction networks (PPINs) of yeast soluble proteins.

Our results showed a clear decrease in both protein size (number of amino acid residues) and fraction of intrinsically disordered residues (disorder content) with increasing protein abundance level. In addition we find that longer proteins contain a higher fraction of disordered residues. Accordingly we also find that more abundant proteins feature a higher Pfam domain coverage. Taken together these results indicate that larger proteins featuring higher level of disorder tend to be avoided as the protein abundance level increases, and that this likely limits non-functional interactions, as the latter tend to be favored by higher protein concentrations (due to mass action).

Next, we investigate the relationships of various sequence properties of the IDRs (such as residue stickiness, hydrophobicity and residue aggregation propensity) with the abundance levels of the corresponding proteins, and compared these properties with those of residues on the surface of globular proteins. This reveals a statistically significant decrease in stickiness of IDR residues with increased protein abundance. This trend is similar to that observed by others (Levy et al.) for surface residues in globular proteins, indicating that IDRs and surfaces of globular proteins may be subjected to a similar selection pressure against forming non-functional interactions.

To proceed we relate the intrinsic properties of yeast proteins, their abundance and disorder content to the patterns of physical and functional interactions they form in a high confidence protein-protein interaction (PPI) network (Collins et al. 2007) involving yeast soluble proteins. Our results confirm that high abundance proteins tend to have more interaction partners (representing ‘hubs’), and that these partners tend to be functionally more diverse (as indicated by a lower average pairwise similarity of their GO annotations). In contrast to previous reports (Haynes et al. in 2006), we find that the majority of the network hubs (55%) correspond to proteins in the 33 percentile lowest disorder level, clearly indicating that hubs of our PPI network tend to be more highly structured, rather then more disordered, and that this discrepancy can be attributed to differences in the underlying PPINs used for the analyses. Our study hence clearly shows that the node degree in the HC yeast PPIN is in fact inversely related to protein disorder, but positively correlated with disorder level of their interaction partners. However we do find that hubs interacting with weakly co-expressed partners tend to be more highly disordered, than hubs interacting with highly co-expressed partners, in reasonable agreement with findings on the different properties of singlish- and multi- interface hubs proposed by Kim et al. (2008).

These results together with a recent analysis of yeast multifunctional proteins provide compelling evidence that while such proteins tend to be enriched in disorder, intrinsic disorder, per se, does not make a protein more prone to forming spurious interactions than their structured counterparts. Hence, structured proteins and those containing higher levels of intrinsic disorder are likely subjected to similar evolutionary pressures to avoid non-functional associations in the cell.