Self-organization and regulation of intrinsically disordered proteins with folded N-termini

Abstract

How do mostly disordered proteins coordinate the specific assembly of very large signal transduction protein complexes? A newly emerging hypothesis may provide some clues towards a molecular mechanism.

Figure 1. Schematic structures of selected large multi-site docking (LMD) protein families involved in signalling.

The Irs/Dok, Gab, p130Cas, and Frs families of LMD proteins provide platforms for assembly of elaborate multi-protein complexes (also known as “signalosomes”) associated with a wide range of cell membrane receptors involved in regulating cell survival, growth, motility, and/or differentiation. They all have a structured N-terminal domain (SNTD) followed by an apparently largely unstructured polypeptide chain. In some cases, short secondary structure motifs like PPII helices, 3₁₀ helices, etc. have been found or are suspected. Many human proteins are predicted to have a similar structural composition (for further details see Figure S2).

Figure 2. Illustration of the N-terminal folding nucleation (NFN) hypothesis.

The NFN hypothesis proposes that, as the nascent chain of an LMD protein (black string) emerges from the ribosome (in grey), the SNTD folds rapidly and spontaneously and then serves as a nucleation core for additional and specific intramolecular protein chain contacts, which generate a more compact protein shape. This compaction may help to avoid proteolysis or aggregation. Instead, the arrangement of docked regions and loops generates defined regions in the protein that may serve as functional subunits. Protein modifications like phosphorylation in some of these defined regions may lead, for example, to the liberation of docked regions, allowing the SNTD to engage in novel types of interactions that might allow the anchorage of the LMD protein in specific subcellular locations. Other modifications are well known to generate docking points for interaction domains of signalling partner proteins, presumably resulting in the rapid assembly of defined sub-complexes on specific loops. Taken together, these features might be expected to increase the ability of cells to respond rapidly and selectively to a diverse set of incoming stimuli.