Intramolecular structural heterogeneity altered by long-range contacts in an intrinsically disordered protein

Gil Koren, Sagi Meir, Lennard Holschuh, Haydyn D.T. Mertens, Tamara Ehm, Nadav Yahalom, Adina Golombek, Tal Schwartz, Dmitri I. Svergun, Omar A. Saleh, Joachim Dzubiella*, Roy Beck*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 and time-resolved Förster resonance energy transfer (trFRET), we study the intramolecular 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 subsegments 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 intramolecular structures. This emphasizes the necessity of advanced polymer theories to fully describe IDPs ensembles with the hope that it will allow us to model their biological function.

Original languageEnglish
Article numbere2220180120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number30
StatePublished - 25 Jul 2023


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