Structural metamorphism and polymorphism in proteins on the brink of thermodynamic stability.

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TitleStructural metamorphism and polymorphism in proteins on the brink of thermodynamic stability.
Publication TypeJournal Article
Year of Publication2018
AuthorsKulkarni, P, Solomon, T, He, Y, Chen, Y, Bryan, PN, Orban, J
JournalProtein Sci
Date Published2018 Aug 24
ISSN1469-896X
Abstract

The classical view of the structure-function paradigm advanced by Anfinsen in the 1960s is that a protein's function is inextricably linked to its three-dimensional structure and is encrypted in its amino acid sequence. However, it is now known that a significant fraction of the proteome consists of intrinsically disordered proteins (IDPs). These proteins populate a polymorphic ensemble of conformations rather than a unique structure but are still capable of performing biological functions. At the boundary between well-ordered and inherently disordered states are proteins that are on the brink of stability, either weakly stable ordered systems or disordered but on the verge of being stable. In such marginal states, even relatively minor changes can significantly alter the energy landscape, leading to large-scale conformational remodeling. Some proteins on the edge of stability are metamorphic, with the capacity to switch from one fold topology to another in response to an environmental trigger (e.g. pH, temperature/salt, redox). Many IDPs, on the other hand, are marginally unstable such that small perturbations (e.g. phosphorylation, ligands) tip the balance over to a range of ordered, partially ordered, or even more disordered states. In general, the structural transitions described by metamorphic fold switches and polymorphic IDPs possess a number of common features including low or diminished stability, large-scale conformational changes, critical disordered regions, latent or attenuated binding sites, and expansion of function. We suggest that these transitions are therefore conceptually and mechanistically analogous, representing adjacent regions in the continuum of order/disorder transitions. This article is protected by copyright. All rights reserved.

DOI10.1002/pro.3458
Alternate JournalProtein Sci.
PubMed ID30144197