Presence of intrinsically disordered proteins can inhibit the nucleation phase of amyloid fibril formation of Aβ(1-42) in amino acid sequence independent manner.

The molecular shield effect was studied for intrinsically disordered proteins (IDPs) that do not adopt compact and stable protein folds. IDPs are found among many stress-responsive gene products and cryoprotective- and drought-protective proteins. We recently reported that some fragments of human genome-derived IDPs are cryoprotective for cellular enzymes, despite a lack of relevant amino acid sequence motifs. This sequence-independent IDP function may reflect their molecular shield effect. This study examined the inhibitory activity of IDPs against fibril formation in an amyloid beta peptide (Aβ(1-42)) model system. Four of five human genome-derived IDPs (size range 20 to 44 amino acids) showed concentration-dependent inhibition of amyloid formation (IC range between 60 and 130 μM against 20 μM Aβ(1-42)). The IC value was two orders of magnitude lower than that of polyethylene-glycol and dextran, used as neutral hydrophilic polymer controls. Nuclear magnetic resonance with  N-labeled Aβ(1-42) revealed no relevant molecular interactions between Aβ(1-42) and IDPs. The inhibitory activities were abolished by adding external amyloid-formation seeds. Therefore, IDPs seemed to act only at the amyloid nucleation phase but not at the elongation phase. These results suggest that IDPs (0.1 mM or less) have a molecular shield effect that prevents aggregation of susceptible molecules.