Unmasking Functional Motifs Within Disordered Regions of Proteins

Abstract

Eukaryotic proteins often possess long stretches that fail to adopt well-defined, three-dimensional structures. These intrinsically disordered regions are associated with cell signaling through the enrichment of hub proteins of networks and as targets for posttranslational modifications. Although disordered regions are readily identified because of their distinct sequence characteristics, it is difficult to predict the functions associated with these regions. This is because disordered regions often house short (two- to five-residue) linear motifs that mediate intermolecular interactions. Predicting their function requires the ability to identify the functionally relevant motifs. If one assumes that functional motifs are highly conserved as compared to background sequence contexts, then a suitable comparative genomics approach proves to be powerful in unmasking functional motifs that are part of disordered regions. This approach has successfully identified known functional motifs and predicted a set of new motifs that might yield important insights regarding previously unknown functionalities for disordered regions. Given knowledge of highly conserved motifs, one can assess whether the rapidly changing sequence contexts are actuators of the functionalities of short linear motifs within disordered regions. This should have important implications for engineering and targeting hub proteins in signaling networks.

Hamiltonian Switch Metropolis Monte Carlo Simulations for Improved Conformational Sampling of Intrinsically Disordered Regions Tethered to Ordered Domains of Proteins

“…In concordance with expectations based on previous reports, 7c,7e,35 IDR1 forms a heterogeneous ensemble of compact, globular conformations as an autonomous unit. Conversely, IDRs 2 and 3 are expected to form semicompact hairpin-like conformations and Flory random coil-like conformations, 7c respectively, and these features are reproduced for these sequences modeled as autonomous units.…”

Cryptic sequence features within the disordered protein p27 Kip1 regulate cell cycle signaling

“…Indeed, their existence was previously postulated (29). Their impact has been established for the C-terminal region of the core subunit of the Polycomb repressive complex 1 that compacts chromatin and inhibits chromatin remodeling (16) and in the Nck system that undergoes phase separation via interactions with polyvalent partners (30).…”

Binding of disordered proteins to a protein hub

“…It is also common for well-structured hub proteins to preferentially interact with disordered partners6. In contrast to protein-protein interactions between well-folded proteins, which usually involve larger interaction surfaces that are discontinuous in sequence, IDPs typically bind to targets using short (~6 residues) consecutive stretches of amino acid residues called linear motifs (LMs)78. These motifs often have distinct sequence characteristics with the primary difference being an increased hydrophobic content9, which may promote local structure formation10111213.…”