Proteins that switch folds

Abstract

An increasing number of proteins demonstrate the ability to switch between very different fold topologies, expanding their functional utility through new binding interactions. Recent examples of fold switching from naturally occurring and designed systems have a number of common features: (i) The structural transitions require states with diminished stability; (ii) Switching involves flexible regions in one conformer or the other; (iii) A new binding surface is revealed in the alternate fold that can lead to both stabilization of the alternative state and expansion of biological function. Fold switching not only provides insight into how new folds evolve, but also indicates that an amino acid sequence has more information content than previously thought. A polypeptide chain can encode a stable fold while simultaneously hiding latent propensities for alternative states with novel functions.

Figure 1

A functional protein can switch into a completely different conformation with a different function via a mutational pathway in which neither function nor native structure is completely lost. The G_A98 and G_B98 proteins are only marginally stable, but restoration of close to wild type stability and function in either direction can be attained with only three mutations (e.g. to G_A88 and G_B88b).

Figure 2

Examples of naturally occurring ordered proteins that can exist in alternatively folded states. The structures of Ltn10, O-Mad2, and CLIC1(reduced) are color-coded as follows: β-strand (cyan), helix (red), and coil (yellow). The structures of the respective alternatively folded states Ltn40, C-Mad2, and CLIC1(oxidized), are shown with an identical per residue color code to illustrate the changes that take place in switching folds. (A) NMR structures of Ltn10 (PDB 1J8I, [54]) and Ltn40 (PDB 2JP1, [8]). A disulfide can be engineered between residues 21 and 59 in Ltn10 to prevent conformational switching. Only one of the subunits is colored in the Ltn40 homodimer. (B) NMR structures of O-Mad2 (PDB 1DUJ; [55]) and C-Mad2 (PDB 1S2H; [26]). Unchanged parts of the structure are in gray. (C) X-ray structures of the reduced (PDB 1K0M, [56]) and oxidized (PDB 1RK4, [31]) forms for the N-domains of CLIC1. The cysteine residues involved in disulfide formation are labeled in both states.

Figure 3

Conformational switching from 3-α G_A to 4 β+α G_B [9,14,15]. Regions of secondary structure in G_B are color coded as follow β-strand (cyan), helix (red), and coil (yellow). The residues corresponding to these regions in the 3-α fold are colored in the same way to illustrate the extent of structural changes.