Intramolecular Structural Heterogeneity altered by Long-range Contacts in an Intrinsically Disordered Protein

TL;DR

This study investigates how long-range contacts influence the structural heterogeneity of intrinsically disordered proteins, revealing that such contacts significantly affect their conformational ensembles and emphasizing the importance of advanced polymer models.

Contribution

It demonstrates that long-range interactions alter IDP conformations beyond local sequence effects, integrating experimental data with polymer physics to better understand IDP structure.

Findings

Flory scaling exponent correlates with net charge of IDP segments.

Segments are more expanded in the full protein context than independently.

Long-range contacts significantly influence IDP conformational heterogeneity.

Abstract

Short-range interactions and long-range contacts drive the 3D folding of structured proteins. The proteins' structure has a direct impact on their biological function. However, nearly 40% of the eukaryotes proteome is composed of intrinsically disordered proteins (IDPs) and protein regions that fluctuate between ensembles of numerous conformations. Therefore, to understand their biological function, it is critical to depict how the structural ensemble statistics correlate to the IDPs' amino acid sequence. Here, using small-angle x-ray scattering (SAXS) and time-resolved F\"orster resonance energy transfer (trFRET), we study the intra-molecular structural heterogeneity of the neurofilament low intrinsically disordered tail domain (NFLt). Using theoretical results of polymer physics, we find that the Flory scaling exponent of NFLt sub-segments correlates linearly with their net charge, ranging from statistics of ideal to self-avoiding chains. Surprisingly, measuring the same segments in the context of the whole NFLt protein, we find that regardless of the peptide sequence, the segments' structural statistics are more expanded than when measured independently. Our findings show that while polymer physics can, to some level, relate the IDP's sequence to its ensemble conformations, long-range contacts between distant amino acids play a crucial role in determining intra-molecular structures. This emphasizes the necessity of advanced polymer theories to fully describe IDPs ensembles with the hope it will allow us to model their biological function.