Charge-induced molecular alignment of intrinsically disordered proteins.

SKORA, L.; CHO, M.; KIM, H.; BECKER, S.; FERNANDEZ, CO; BLACKLEDGE, M.; ZWECKSTETTER, M.

Angewandte Chemie (International ed. in English)

Año: 2006 vol. 45 p. 7012 - 7015

1433-7851

Intrinsically disordered or unstructured proteins (IUPs) play key roles in normal and pathological biochemical processes. Despite their importance for function, this category of proteins remains beyond the reach of classical structural biology because of their inherent conformational heterogeneity. Measurements of global dimensions strongly suggested a random coil like behaviour of IUPs. In contrast to these findings, NMR spectroscopy detected significant amounts of local structure in denatured and unfolded states. We have demonstrated that the assumption of a steric-like interaction between intrinsically disordered proteins and the alignment medium is only valid in case of uncharged alignment media. Alignment of IUPs in charged media depends critically on electrostatic interactions, especially in charged regions of the protein, scales with ionic strength of the solution and can be predicted using a simplified electrostatic model. Our work demonstrate that molecular alignment of intrinsically unstructured and other disordered proteins in charged nematic media strongly depends on electrostatic interactions between the protein and the alignment medium. A simple electrostatic alignment model reliably predicts RDCs under different sample conditions. Electrostatic effects have to be taken into account when using RDCs for the interpretation of residual structure in disordered proteins. At the same time, however, charge-modulation of alignment provides an independent set of RDCs in disordered proteins, potentially improving the structural characterization of these systems. These findings have important consequences for the RDC-based interpretation of the structure and dynamics of the unfolded state.