The cellular environment therefore represents a rather unusual condition quite unlike an ideal solution. These macromolecules occupy approximately 30% of the cellular volume, suggesting that steric exclusion imposed by a lack of space in solution must result in significant thermodynamic alterations in proteins. For example, a typical cell may contain ~ 25% protein by volume, in addition to certain amounts of RNA 1, 2. In living cells, almost all proteins must co-exist with other proteins and other biological molecules, such as nucleic acids and phospholipid vesicles, which are present at extremely high concentrations. These results suggest that IDPs (0.1 mM or less) have a molecular shield effect that prevents aggregation of susceptible molecules. Therefore, IDPs seemed to act only at the amyloid nucleation phase but not at the elongation phase. The inhibitory activities were abolished by adding external amyloid-formation seeds. Nuclear magnetic resonance with 15 N-labeled Aβ(1–42) revealed no relevant molecular interactions between Aβ(1–42) and IDPs. The IC 50 value was two orders of magnitude lower than that of polyethylene-glycol and dextran, used as neutral hydrophilic polymer controls.
Four of five human genome-derived IDPs (size range 20 to 44 amino acids) showed concentration-dependent inhibition of amyloid formation (IC 50 range between 60 and 130 μM against 20 μM Aβ(1–42)). This study examined the inhibitory activity of IDPs against fibril formation in an amyloid beta peptide (Aβ(1–42)) model system. This sequence-independent IDP function may reflect their molecular shield effect. 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. IDPs are found among many stress-responsive gene products and cryoprotective- and drought-protective proteins. The molecular shield effect was studied for intrinsically disordered proteins (IDPs) that do not adopt compact and stable protein folds.