Turncoat Polypeptides: We Adapt to Our Environment

Abstract

A common interpretation of Anfinsen's hypothesis states that one amino acid sequence should fold into a single, native, ordered state, or a highly similar set thereof, coinciding with the global minimum in the folding‐energy landscape, which, in turn, is responsible for the function of the protein. However, this classical view is challenged by many proteins and peptide sequences, which can adopt exchangeable, significantly dissimilar conformations that even fulfill different biological roles. The similarities and differences of concepts related to these proteins, mainly chameleon sequences, metamorphic proteins, and switch peptides, which are all denoted herein “turncoat” polypeptides, are reviewed. As well as adding a twist to the conventional view of protein folding, the lack of structural definition adds clear versatility to the activity of proteins and can be used as a tool for protein design and further application in biotechnology and biomedicine.

Evolution of fold switching in a metamorphic protein

“…Metamorphic proteins undergo large-scale structural changes (e.g., alterations in secondary structure and hydrogen bonding networks), whereas allosteric proteins exhibit smaller-scale conformational dynamics (1,2). Whereas only about six metamorphic proteins have been well characterized (2)(3)(4), estimates suggest that metamorphic proteins may constitute up to 4% of proteins in the Protein Data Bank (PDB) (5). The emergence of new protein folds on evolutionary time scales has been examined (6)(7)(8)(9), but it remains unclear how metamorphic folding evolves in a single protein.…”

Insights Into the Micelle-Induced β-Hairpin-to-α-Helix Transition of a LytA-Derived Peptide by Photo-CIDNP Spectroscopy

“…For instance, fluorescence gives information about tryptophan sidechains [18] but not Tyr sidechains. On the whole, our results open new avenues for interpreting conformational transitions, such as the case of switch [9][10][11] and self-associating peptides [36] and render valuable information for combating structural changes that cause virulence and pathogenesis. The high-power LED was controlled by an electronic circuit that consisted of a power supply, the LED (Cree XT-E LED, US, with a center wavelength of 455 nm and 500 mW optical output power), a potentiometer to regulate the current through the LEDs, and a transistor switched by a TTL signal from the time control unit of the spectrometer.…”

“…A common aspect to all the above findings is that a particular amino acid sequence acts as a "conformational switch", enabling different secondary structures under distinct environments [9][10][11], i.e., pH/temperature changes or interactions with other molecules [12]. This feature makes chameleonic sequences very suitable for protein folding and design [13,14], with boundless applications ranging from the delivery of new therapeutics that block or promote these transitions [15] to the design of novel biosensors [16].…”

Structural and thermodynamic analyses of the β-to-α transformation in RfaH reveal principles of fold-switching proteins

“…To date about six fold-switching proteins have been studied in detail (summarized in refs. (Dishman and Volkman, 2018; Lella and Mahalakshmi, 2017; Zamora-Carreras et al, 2020)), but estimates suggest that up to 4 % of the proteins in the PDB may have the ability to switch folds (Porter and Looger, 2018). Our study demonstrates which molecular mechanisms confer RfaH its structural plasticity that allows operon-specific regulation without competing with its monomorphic paralog NusG/Spt5.…”