A new study led by the Ohio State University (OSU) has shed more light on the structure and functioning of plastins – a type of proteins found in many life forms (from yeast and plants to animals and humans) that have a role in ensuring that various cells move or maintain their shape. By binding to and bundling other proteins, plastins can be considered the bones and muscles of cells. Better understanding what drives their activities could help explain their surprising links to diseases such as cancers, congenital osteoporosis, or spinal muscular atrophy.
Scientists described their discoveries about plastin behavior in terms of a “work-life balance” metaphor. While in their “at-home” mode, the protein’s two main segments strongly bond to each other, they are often forced to separate when their bundling responsibilities in the cellular “workplace” increase, such as when cells start to migrate. According to the researchers, if their structure experiences unexpected changes, plastins keep doing aggressive bundling work, even if it is not needed anymore. Although experts discovered at least one mistimed enzymatic activity that seemed to contribute to this problem, further research is needed to fully understand the mechanisms behind the switch between the protein’s “weekend” and “workaholic” modes.
“We need to know this information so we can figure out how to regulate plastins,” said study senior author Dmitri Kudryashov, an associate professor of Chemistry and Biochemistry at OSU. “Because plastins are involved in disease, we see the manifestation of that, but we don’t know how precisely mutations lead to disease. In cancer, or certain autoimmune reactions, knowing exactly what plastins do and how to control their activity could be highly beneficial. If we could manage to inhibit this protein in cancer, it’s likely the cells would become less invasive.”
Actins – abundant proteins helping cells unite their contents, maintain their shape, divide, and migrate – are clustered together by plastins configured with two binding sites, each of which can bind to actin filaments. However, when these binding domains are tightly joined, they can connect only weakly to actins. If cells are stable, connecting in this way is sufficient, but when cells start to migrate, actins pushed in the direction of cell movement are situated in a less organized way that requires strong connections to plastins. In such a case, plastin’s binding domains have to separate from each other to form a stronger bond to actins. Eventually, actins shifting away from the cell’s edge no longer need a strong plastin bond, so plastin can return to its self-engaged “weekend” mode.
By introducing a mutation to plastin which mimics molecular changes detected in cancer cells, the scientists found that such a mutation prolonged plastin binding sites’ disengagement, and caused plastins to keep try to bundle up actins that don’t need to be bundled anymore. In such a case, plastin’s lack of response to what cells need could have undesirable downstream effects.
Further research is needed to clarify which factors may lead to this “irrational” behavior of plastins in order to shed more light on how these essential proteins contribute to disease.
The study is published in the journal Nature Structural & Molecular Biology.