Disorder transitions and conformational diversity cooperatively modulate biological function in proteins

Abstract

Structural differences between conformers sustain protein biological function. Here, we studied in a large dataset of 745 intrinsically disordered proteins, how ordered-disordered transitions modulate structural differences between conformers as derived from crystallographic data. We found that almost 50% of the proteins studied show no transitions and have low conformational diversity while the rest show transitions and a higher conformational diversity. In this last subset, 60% of the proteins become more ordered after ligand binding, while 40% more disordered. As protein conformational diversity is inherently connected with protein function our analysis suggests differences in structure-function relationships related to order-disorder transitions.

Homology modeling in a dynamical world

“…Because it is difficult to predict the extent of CD in a given protein, we used the presence of disordered regions as an indicator of higher values of CD, based upon previous results. 38 We found that the presence of highly ordered proteins (without any disordered regions in any conformer) in pairs of homologous proteins have a Spearman's correlation rho of 20.58 for RMSD and a sequence identity relationship. In this way, we found that presence of disorder/order is not a strong indicator of a well-correlated sequence and structural change (Fig.…”

“…It is difficult to estimate the extent of flexibility in the disordered regions, but it is possible to measure conformational diversity in the ordered regions of these proteins using the RMSD between different conformers, for example . We found that proteins containing IDRs have larger conformational diversity than those with full ordered structures, when disorder‐order transitions take place between protein conformations . Furthermore, we recently found that proteins with IDRs can be split into two groups with different structure‐function relationships, depending on how structure‐based features change among the available conformer population for each protein .…”

“…Our results indicate that the relative success of the 3D model using TBM approaches will be strongly associated with the CD of the corresponding target protein. Because it is difficult to predict the extent of CD in a given protein, we used the presence of disordered regions as an indicator of higher values of CD, based upon previous results . We found that the presence of highly ordered proteins (without any disordered regions in any conformer) in pairs of homologous proteins have a Spearman's correlation rho of −0.58 for RMSD and a sequence identity relationship.…”

“…However, our previous work shows that proteins with disordered regions have larger conformational diversity compared with ordered proteins, on average. 38 In the section "How does protein disorder correlate with SD?," we address this question: How is protein disorder related to SD?…”

“…42 We found that proteins containing IDRs have larger conformational diversity than those with full ordered structures, when disorder-order transitions take place between protein conformations. 38 Furthermore, we recently found that proteins with IDRs can be split into two groups with different structure-function relationships, depending on how structure-based features change among the available conformer population for each protein. 43 Therefore, it is interesting to ask if the structure-sequence relationship could be also separated into two groups, mainly proteins with and without IDRs, following the above-mentioned results using CD.…”