Intrinsically disordered proteins (IDPs) are characterised by poly-peptide chains that fail to fold into stable and well defined tertiary structure. In spite of the lack of stable structure, IDPs play key roles in processes such as molecular recognition, regulation of transcription and they are related to neurodegenerative diseases. Although structural characterisation of this class of proteins is highly desirable, standard, single conformer-based approaches to structure determination necessarily fail to adequately describe such highly flexible systems. It is therefore essential to use other methods to determine local and long-range structural behaviour in IDPs from experimental nuclear magnetic resonance (NMR) and small-angle X-ray scattering (SAXS) data. In particular, we used the ASTEROIDS (A Selection Tool for Ensemble Representations Of Intrinsically Disordered States) algorithm that selects representative structural ensembles of IDPs on the basis of complementary experimental data sets following the evolution scheme of a genetic algorithm. We have applied these approach to study microtubule-associated protein 2c (MAP2c) and the δ subunit of RNA polymerase. Both proteins play important physiological roles. The δ subunit is required for rapid changes in gene expression and competitive fitness of the cell, MAP2c regulates the dynamics of microtubules in developing neurons. These biological functions require a carefully controlled balance between high flexibility and ability to form transient secondary structures and long-range contacts. Our conformational analysis revealed such structural features and showed that so-called IDPs exhibit clear structure-function relationship.
This work was supported by the Ministry of Education, Youth and Sports of the Czech Republic under the National Sustainability Programme II, project CEITEC 2020 (LQ1601), and by the Inter-Excellence Inter-Cost project LTC17078.