Linking folding and binding

Abstract

Many cellular proteins are intrinsically disordered and undergo folding, in whole or in part, upon binding to their physiological targets. The past few years have seen an exponential increase in papers describing characterization of intrinsically disordered proteins, both free and bound to targets. Although NMR spectroscopy remains the favored tool, a number of new biophysical techniques are proving exceptionally useful in defining the limits of the conformational ensembles. Advances have been made in prediction of the recognition elements in disordered proteins, in elucidating the kinetics and mechanism of the coupled folding and binding process, and in understanding the role of post-translational modifications in tuning the biological response. Here we review these and other recent advances that are providing new insights into the conformational propensities and interactions of intrinsically disordered proteins and are beginning to reveal general principles underlying their biological functions.

Figure 1

Structural comparison of the NCBD (IbID) domain of CBP in complex with different partners. A. NCBD in complex with the ACTR domain of p160 [28]. B. NCBD in complex with IRF3 [29].

Figure 2

Schematic showing the two possibilities, folding upon binding or conformational selection.

Figure 3

Schematic representation of the induced folding mechanism of pKID binding to KIX [32], derived from NMR relaxation dispersion measurements. The conformational ensemble of the free protein contains little propensity for helical structure; the initial encounter complex is heterogeneous and mostly involves the C-terminal end of the pKID peptide. The intermediate structure shows contact between KIX and the entire length of the peptide, but helical structure is not present in either α_A or α_B. Finally the fully folded complex shows stable helical structure in both regions of pKID. (adapted with permission from Nature NV).