Discovery of a new evolutionarily conserved short linear F-actin binding motif

Paraschiakos, T.; Yuan, B.; Sopelniak, K.; Bucher, M.; Simon, L.; Zonjic, K.; Eggers, D.; Selle, F.; Li, J.; Linder, S.; Marlovits, T. C.; Windhorst, S.

doi:10.1101/2025.04.16.649135

bioRxiv · 10.1101/2025.04.16.649135

Discovery of a new evolutionarily conserved short linear F-actin binding motif

Paraschiakos, T.·Yuan, B.·Sopelniak, K.·Bucher, M.·Simon, L.·Zonjic, K.·Eggers, D.·Selle, F.·Li, J.·Linder, S.·Marlovits, T. C.·Windhorst, S.

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Abstract

Regulation of the actin cytoskeleton by actin binding proteins (ABPs) is essential for cellular homeostasis, and the mode of actin binding determines the activity of ABPs. Here, we discovered a novel "Short linear F-actin binding motif (SFM)" on the basis of the cryo-EM structure of the ITPKA-F-actin complex. We developed the computational pipeline SLiMFold, which identified 103 human SFM containing-proteins exhibiting diverse cellular functions. The SFM probably developed ex nihilo and remained conserved in eukaryotes, with a binding affinity to F-actin ranging from 13 to 89 {micro}M. Furthermore, we uncovered the essential amino acids of this SFM for F-actin binding and affinity modulation. Together, the SFM seems to serve as a low affinity anchor to target proteins to F-actin, in order to connect the regulation of actin dynamics with broad cellular functions. These findings will shed new light on the role of a wide variety of proteins.

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Paraschiakos, T., Yuan, B., Sopelniak, K., Bucher, M., Simon, L., Zonjic, K., Eggers, D., Selle, F., Li, J., Linder, S., Marlovits, T. C., Windhorst, S.. 2025-04-16. Discovery of a new evolutionarily conserved short linear F-actin binding motif. https://doi.org/10.1101/2025.04.16.649135

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