Many proteins consist of more than just rigid, precisely folded components. They also contain flexible sections, so-called intrinsically disordered regions, or IDRs for short, which do not form a stable three-dimensional structure and yet take on central tasks in the cell.
“Such disordered protein domains make up around a third of all protein structures and have recently come into particular focus because it has become clear that they enter into particularly diverse interactions, can form biomolecular condensates and are involved in practically all essential cell functions,” explains Professor Philipp Korber, group leader at the Chair of Molecular Biology at the LMU Biomedical Center.
It is precisely these disordered areas that have long puzzled researchers: their linear amino acid sequence often changes significantly in the course of evolution, although their function remains the same. A new study that recently appeared in the journal Nature Cell Biology now shows how this apparent contradiction can be explained. Two properties that work together are crucial: the precise, linear sequence of individual amino acids and the overarching chemical characteristics of the entire region.
Flexible sections with important tasks
For their work, the researchers from LMU, Technical University of Munich (TUM), Helmholtz Munich and Washington University in St. Louis, USA, examined an essential disordered protein segment of the yeast protein Abf1. Using this easy-to-manipulate model system, they systematically tested over 150 Abf1 variants, which modified and sometimes completely newly designed sequences can replace the function of the natural section.
This showed that, on the one hand, short binding motifs play an important role – i.e. small linear sequence sections that enable very specific molecular contacts. On the other hand, it depends on the overall chemical context, such as the content of negative charges and water-soluble or poorly soluble amino acids within the disordered region. Only the interaction of both aspects, the linear motifs and the overarching chemical context, decides whether the protein region is functional.
“Intrinsically disordered regions seem contradictory at first glance: they are biologically very important, but can often only be inadequately explained using classical sequence comparisons,” says Korber, who led the study together with Alex Holehouse, Professor of Biochemistry and Molecular Biophysics at Washington University. “Our results show that their function does not depend on a conserved linear blueprint, but rather arises from the variable interaction of different proportions of linear sequence motifs and physicochemical properties.”
When chemistry makes up for a missing motive
What was particularly surprising was a finding that goes beyond the specific model system: a binding motif that is indispensable in the naturally evolved protein region can become unnecessary under certain conditions. This is because the chemical properties of the surrounding sequence context can be changed in such a way that they compensate for the loss of function. Conversely, it is not enough to simply maintain the rough composition of a region if the crucial motif is destroyed or the chemical context is unfavorable. The study thus makes it clear that IDRs operate on a type of functional landscape in which different molecular solutions can lead to the same result.
“This significantly expands the space of possible functioning sequences,” says Korber. “Evolution of intrinsically disordered regions can apparently use different molecular strategies and still maintain the same biological function. This helps us understand why these protein regions can be so variable over the course of evolution without losing their function.”
New perspectives
The work thus provides a general framework for better understanding the evolution of disordered protein regions. At the same time, it opens up new perspectives for biomedical research. Many disease-relevant changes affect precisely such flexible protein sections, the significance of which has so far been difficult to assess. If their function does not result from an exact sequence alone, but from an interplay of motifs and chemical properties, this could help in the future to assess mutations more precisely and to design artificial proteins more specifically.
Source: Ludwig Maximilian University of Munich
Original publication: Langstein-Skora et al.; Sequence and chemical specificity define the functional landscape of intrinsically disordered regions; Nature Cell Biology 282026, DOI: 10.1038/s41556-025-01867-8
