Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

Abstract

Molecular recognition features (MoRFs) are intrinsically disordered protein regions that bind to partners via disorder-to-order transitions. In one-to-many binding, a single MoRF binds to two or more different partners individually. MoRF-based one-to-many protein-protein interaction (PPI) examples were collected from the Protein Data Bank, yielding 23 MoRFs bound to 2-9 partners, with all pairs of same-MoRF partners having less than 25% sequence identity. Of these, 8 MoRFs were bound to 2-9 partners having completely different folds, whereas 15 MoRFs were bound to 2-5 partners having the same folds but with low sequence identities. For both types of partner variation, backbone and side chain torsion angle rotations were used to bring about the conformational changes needed to enable close fits between a single MoRF and distinct partners. Alternative splicing events (ASEs) and posttranslational modifications (PTMs) were also found to contribute to distinct partner binding. Because ASEs and PTMs both commonly occur in disordered regions, and because both ASEs and PTMs are often tissue-specific, these data suggest that MoRFs, ASEs, and PTMs may collaborate to alter PPI networks in different cell types. These data enlarge the set of carefully studied MoRFs that use inherent flexibility and that also use ASE-based and/or PTM-based surface modifications to enable the same disordered segment to selectively associate with two or more partners. The small number of residues involved in MoRFs and in their modifications by ASEs or PTMs may simplify the evolvability of signaling network diversity.

The Catalytic Efficiency of Lipin 1β Increases by Physically Interacting with the Proto-oncoprotein c-Fos

“…11). The regions with increased order propensity are often found to be functional domains within disordered proteins and participate in the molecular recognition of multiple binding targets (55).…”

Dancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Disordered Proteins

“…Although a portion of such folding code is missing for IDPs, it can be supplemented by their binding partner(s) (14). Curiously, because different binding partners could provide drastically different complementary parts of a folding code, an IDP/IDPR can fold differently at binding to different partners (15,16). Based on these considerations, it has been hypothesized that IDPs/IDPRs should be considered as "edge of chaos" systems that operate in the boundary between order and complete randomness or chaos, i.e.…”

“…In its bound state, a MoRF constitutes a short, contiguous, (partially) structured segment fitted into a groove at the surface of the ordered partner. Morphing MoRFs correspond to a subset of MoRFs characterized by the polymorphism of their bound states, where a bound region adopts completely different geometries in the rigidified structures induced by the binding to its partner, depending on the nature of the bound partner (15,16,19,55,56).…”

Discriminating binding mechanisms of an intrinsically disordered protein via a multi-state coarse-grained model

“…[18][19][20] This question is most relevant when the bound conformation is not already the dominant population in the unbound state. Of particular interest are those IDPs that are able to interact with a) Electronic mail: robertbe@helix.nih.gov multiple binding partners, 21 sometimes even adopting a different folded structure in the context of a different binding partner. 20,21 The distinction between these two binding mechanisms may seem somewhat ill-defined: on the one hand, the bound state must always exist with some finite probability even in the absence of the partner, while on the other hand, the presence of the binding partner would be expected to favour a transition to the bound conformation, if binding is favourable.…”