Protein domain definition should allow for conditional disorder

Abstract

Proteins are often classified in a binary fashion as either structured or disordered. However this approach has several deficits. Firstly, protein folding is always conditional on the physiochemical environment. A protein which is structured in some circumstances will be disordered in others. Secondly, it hides a fundamental asymmetry in behavior. While all structured proteins can be unfolded through a change in environment, not all disordered proteins have the capacity for folding. Failure to accommodate these complexities confuses the definition of both protein structural domains and intrinsically disordered regions. We illustrate these points with an experimental study of a family of small binding domains, drawn from the RNA polymerase of mumps virus and its closest relatives. Assessed at face value the domains fall on a structural continuum, with folded, partially folded, and near unstructured members. Yet the disorder present in the family is conditional, and these closely related polypeptides can access the same folded state under appropriate conditions. Any heuristic definition of the protein domain emphasizing conformational stability divides this domain family in two, in a way that makes no biological sense. Structural domains would be better defined by their ability to adopt a specific tertiary structure: a structure that may or may not be realized, dependent on the circumstances. This explicitly allows for the conditional nature of protein folding, and more clearly demarcates structural domains from intrinsically disordered regions that may function without folding.

Molecular Basis for Structural Heterogeneity of an Intrinsically Disordered Protein Bound to a Partner by Combined ESI-IM-MS and Modeling

“…The experimental mass (6554.28±0.04 Da) corresponds to the value calculated from the amino acid sequence of the protein without the initial methionine (6555.66 Da). The conformational heterogeneity adopted by MeV P XD is in agreement with previous biophysical and structural studies on the homologous phosphoprotein X domains from members of the closely related Rubulavirus genus, indicating that these domains span a structural continuum, ranging from compact to largely disordered states in solution [67,68].…”

Protein folding and stability in the presence of osmolytes

“…Such proteins can form compact regular structures only during interactions with their partners [102]. A number of studies have indicated the possibility that native disordered proteins can assume a compact regular structure in osmolyte solutions without interacting with their corresponding partners [66,[103][104][105][106]. As an example, a study on RNAse P [66] uncovered the fact that the native protein structure in a complex with RNA and the structure that emerges during renaturation of this protein in TMAO solution are similar but not identical, while the paths by which this protein folds in the presence of RNA and it is absence, but in the presence of TMAO, are considerably different.…”

Digested disorder, Quarterly intrinsic disorder digest (October-November-December, 2013)

“…4 A study by Yegambaram et al 5 used a family of small binding domains existing in various structural states, which were able to adopt the same tertiary structure given the proper conditionals. The authors argued for a conditional disorder domain classification, where a domain is defined by its potential to adopt a certain structure, given environmental conditions.…”

“…As in the previous issues, no special filtering was used except to verify the print date, and exclude those papers not related to the topic. The digest article is structured hierarchically and papers are grouped in several sections: (1) structures of intrinsically disordered proteins (IDPs); (2) functions of IDPs; (3) methods for the IDP analysis; (4) proteomics of IDPs; (5) IDPs and diseases; and (6) IDPs/IDPRs as drugs or drug targets. One should keep in mind that the unambiguous classification of many papers is challenged by the intertwining of topics they cover.…”