"Natively unfolded" proteins occupy a unique niche within the protein kingdom in that they lack ordered structure under conditions of neutral pH in vitro. Analysis of amino acid sequences, based on the normalized net charge and mean hydrophobicity, has been applied to two sets of proteins: small globular folded proteins and "natively unfolded" ones. The results show that "natively unfolded" proteins are specifically localized within a unique region of charge-hydrophobicity phase space and indicate that a combination of low overall hydrophobicity and large net charge represent a unique structural feature of "natively unfolded" proteins.

Why are "natively unfolded" proteins unstructured under physiologic conditions?

The experimental material accumulated in the literature on the conformational behavior of intrinsically unstructured (natively unfolded) proteins was analyzed. Results of this analysis showed that these proteins do not possess uniform structural properties, as expected for members of a single thermodynamic entity. Rather, these proteins may be divided into two structurally different groups: intrinsic coils, and premolten globules. Proteins from the first group have hydrodynamic dimensions typical of random coils in poor solvent and do not possess any (or almost any) ordered secondary structure. Proteins from the second group are essentially more compact, exhibiting some amount of residual secondary structure, although they are still less dense than native or molten globule proteins. An important feature of the intrinsically unstructured proteins is that they undergo disorder–order transition during or prior to their biological function. In this respect, the Protein Quartet model, with function arising from four specific conformations (ordered forms, molten globules, premolten globules, and random coils) and transitions between any two of the states, is discussed.

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Natively unfolded proteins: a point where biology waits for physics.

Understanding protein non-folding.

Conformational constraints for amyloid fibrillation: the importance of being unfolded.

Natively unfolded or intrinsically unstructured proteins constitute a unique group of the protein kingdom. The evolutionary persistence of such proteins represents strong evidence in the favor of their importance and raises intriguing questions about the role of protein disorders in biological processes. Additionally, natively unfolded proteins, with their lack of ordered structure, represent attractive targets for the biophysical studies of the unfolded polypeptide chain under physiological conditions in vitro. The goal of this study was to summarize the structural information on natively unfolded proteins in order to evaluate their major conformational characteristics. It appeared that natively unfolded proteins are characterized by low overall hydrophobicity and large net charge. They possess hydrodynamic properties typical of random coils in poor solvent, or premolten globule conformation. These proteins show a low level of ordered secondary structure and no tightly packed core. They are very flexible, but may adopt relatively rigid conformations in the presence of natural ligands. Finally, in comparison with the globular proteins, natively unfolded polypeptides possess 'turn out' responses to changes in the environment, as their structural complexities increase at high temperature or at extreme pH.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.0014-2956.2001.02649.x

What does it mean to be natively unfolded

Prothymosin alpha has previously been shown to be unfolded at neutral pH, thus belonging to a growing family of "natively unfolded" proteins. The structural properties and conformational stability of recombinant human prothymosin alpha were characterized at neutral and acidic pH by gel filtration, SAXS, circular dichroism, ANS fluorescence, (1)H NMR, and resistance to urea-induced unfolding. Interestingly, prothymosin alpha underwent a cooperative transition from the unfolded state into a partially folded conformation on lowering the pH. This conformation of prothymosin alpha is a compact denatured state, with structural properties different from those of the molten globule. The formation of alpha-helical structure by the glutamic acid-rich elements of the protein accompanied by the partial hydrophobic collapse is expected at lower pH due to the neutralization of the negatively charged residues. It is possible that such conformational changes may be associated with the protein function.

Galina D. Kozlovskaya

Papers

Natively unfolded human prothymosin alpha adopts partially folded collapsed conformation at acidic pH.

Zn2+-Mediated Structure Formation and Compaction of the “Natively Unfolded” Human Prothymosin α