New LMU research shows how proteins can function reliably even without a stable 3D structure, showing that not only short sequence motifs but also chemical properties are critical.
Many proteins are not only composed of stably folded building blocks. They also contain flexible parts known as intrinsically disordered regions (IDRs) that do not form stable three-dimensional structures but play important roles within cells.
Such disordered protein domains constitute approximately one-third of all protein structures. Recently, they have attracted significant attention, especially as it has been revealed that they are involved in diverse interactions, can form biomolecular condensates, and are involved in virtually all major cellular functions. ”
Professor Philip Kober, Group Leader, Molecular Biology Department, LMU Biomedical Center
These chaotic regions have long puzzled researchers. Their linear amino acid sequences are often poorly conserved during evolution, even though their function remains the same. New research recently published in journals natural cell biologyresolves this apparent contradiction. According to the authors, different combinations of two properties are decisive: linear amino acid sequences in short stretches (motifs) and chemical signatures across larger regions.
Flexible segments play a key role
For this study, researchers from LMU München, Technical University of Munich (TUM), Helmholtz München, and Washington University in St. Louis investigated an essential disordered protein segment of the yeast protein Abf1. Using this easy-to-operate model system, they systematically experimented with more than 150 Abf1 mutants to see which modified sequences, and in some cases newly designed sequences, could replace the functionality of the native segment. Their results showed that short binding motifs, small linear sequence segments that enable highly specific molecular contacts, play an important role. They found that another important contribution comes from the overall chemical context, such as negative charges and the amount of water-soluble or sparingly soluble amino acids within the disordered region. It is the interaction of these two aspects, the linear motif and the broader chemical context, that determines whether a protein region is functional.
“Intrinsically disordered regions seem contradictory at first glance. They are of great biological importance, but are often not fully explained by classical sequence comparisons,” says Professor Kober, who led the study with Alex Holhaus, professor of biochemistry and molecular biophysics at the University of Washington. “Our results show that their function does not depend on a conserved linear blueprint, but on a variable interplay of different proportions of linear sequence motifs and physicochemical properties.”
When chemistry balances non-existent motifs
Particularly surprising were the findings that were relevant beyond specific model systems. This means that binding motifs that are essential to naturally evolved protein regions may become unnecessary under certain conditions. This is because the chemical properties of the surrounding sequence context can be modified to offset the loss of function. Conversely, preserving the rough composition of a region is not sufficient if important motifs are disrupted or the chemical conditions are unfavorable. Therefore, this study revealed that IDRs operate in a kind of functional landscape where different molecular solutions can lead to the same outcome.
“This greatly expands the space of possible functional sequences,” Kober points out. “The evolution of intrinsically disordered regions clearly uses different molecular strategies to maintain the same biological function. This helps us understand why these protein regions can change so much over the course of evolution without loss of function.”
New perspectives on evolutionary biology and evolutionary medicine
This study therefore provides a general framework to better understand the evolution of disordered protein regions. At the same time, it brings new perspectives to biomedical research. Many disease-related changes affect these flexible protein segments, but their significance has so far been difficult to assess. If their function arises from the interaction of motifs and chemical features, rather than from the precise sequence alone, it could help researchers better interpret mutations and design synthetic proteins in a more targeted way in the future.
sauce:
Ludwig Maximilian University of Munich
Reference magazines:
Langstein-Schola, I. others. (2026). Sequence and chemical specificity define the functional landscape of an inherently disordered region. Cell Biology of Nature. DOI: 10.1038/s41556-025-01867-8. https://www.nature.com/articles/s41556-025-01867-8
