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26. June 2025
Scientists from CEITEC Masaryk University, in collaboration with the Czech Academy of Sciences and the University of Regensburg, have identified a novel mechanism by which proteins interact inside human cells. Their discovery reveals that a protein segment (ligand) can bind to its partner in two different modes while constantly switching between them. These findings challenge long-held assumptions about how protein interactions are regulated and could reshape our understanding of cell communication (signalling). The research could help pave the way for new treatment strategies by targeting protein communication in certain types of disease.
The study, published in Structure, focuses on a small module found in many proteins, known as the PDZ domain. PDZ domains act like docking stations, allowing one protein to bind to specific short sequences (called ligands) typically located at the ends of other proteins. These interactions help organize protein networks that control processes like cellular architecture, signalling pathways, and intracellular communication.
The researchers investigated the PDZ domain of one specific protein called Dishevelled (DVL), a key protein in the Wnt signalling pathway. This pathway regulates essential processes such as embryo development, tissue regeneration, and cell division. Disruptions in Wnt signalling are associated with cancer and developmental disorders.
What the team discovered was unexpected: a short segment from the C-terminal (tail-end) of DVL can bind to its PDZ domain in two distinct ways. Instead of locking into a single position, the ligand dynamically switches between two configurations: one using its terminal motif (binding site) and the other using an internal motif further upstream in the sequence. This phenomenon, called a dual binding mode, challenges the classic view that protein-protein interactions follow a single, fixed pattern. Instead, it reveals a surprising degree of flexibility and the ability of a single sequence to adopt multiple functional roles.
“This flexibility appears to be encoded in the sequence itself and may serve as a built-in regulatory switch that controls when the protein becomes active, e.g. in response to modifications that happen after the protein is produced, such as phosphorylation or polyglutamylation,” says Jitender Kumar, first author of the study.
According to Konstantinos Tripsianes, head of the Protein-DNA Interactions group at CEITEC and senior author of the study, “this switching behaviour could function as an internal regulatory system that allows the protein to respond to specific cellular signals. Such responsiveness is vital for maintaining precision in cell signalling.”
The team also analysed over 500 known PDZ structures and found that a similar dual binding mode could occur more widely. Their results suggest that dynamic switching of binding modes may be a general strategy that cells use to fine-tune interactions between proteins.
Understanding how proteins communicate within cells opens the door to developing smarter therapeutic approaches, especially for diseases where the regulation of protein interactions has gone awry.
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