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Four-helical bundle segmentation strategy

 

Designed protein-protein interactions provide a great tool for developing diverse applications in synthetic biology and biomedicine. To expand oligomerization possibilities researchers from the Department of synthetic biology and Immunology at the National Institute of Chemistry present a segmentation strategy of a single four-helical bundle protein (4HB). 4HB can be divided into two or up to four segments in different ways (1:3, 2:2, 1:2:1, 1:1:1:1) defining up to 4 interacting molecules. Newly designed oligomerization modules have been implemented in the regulation of mammalian cells, for enzyme reconstitution, gene expression, or CAR-T cell regulation. The results were published as a research article titled Segmentation strategy of de novo designed four-helical bundles expands protein oligomerization modalities for cell regulation in the prestigious scientific journal Nature Communications.

In recent years the technology of de novo protein design provided great advancement in the synthetic biology field. However, the de novo design of small helical structures like coiled-coil or four helical bundles (4HB) has limitations. Due to a limited number of amino acids, short sequences, and strict rules for amino acid selection onto specific positions, de novo design can provide a restricted size or orthogonal set of such structures. To overcome these limitations a novel segmentation method of 4HB conveyed the possibility to generate diverse oligomerization domains from a single 4HB.

To expand the versatility of the designed oligomerization domains, they implemented the investigated segmentations of 4HBs for various biological processes as synthetic tools: transcriptional regulators, protease-regulated dimerization modules and protease cascade arrangement, chemically inducible trimerization modules and dual CAR‑T modules for engineering different combinations for arming T cells against cancer cells.

The research article encompasses experimental work that took place at the Department of Synthetic Biology and Immunology at the National Institute of Chemistry, mainly by a Ph.D. student Estera Merljak and was led by Prof. Dr. Roman Jerala. The authors of the study are Estera Merljak, Benjamin Malovrh, and Roman Jerala.

Merljak, E., Malovrh, B. & Jerala, R. Segmentation strategy of de novo designed four-helical bundles expands protein oligomerization modalities for cell regulation. Nat Commun14, 1995 (2023). https://doi.org/10.1038/s41467-023-37765-6

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