Plenary Talk 21st International Conference on Biological Inorganic Chemistry 2025

3D domain swapping of metalloproteins (122514)

Shun Hirota 1
  1. Nara Institute of Science and Technology, Ikoma, Nara, Japan

     Metalloproteins are responsible for many biological reactions; thus, the construction of protein assemblies will increase the use of metalloproteins. Three-dimensional (3D) domain swapping is a protein oligomerization phenomenon that exchanges the same domain or secondary structural element between molecules. 3D domain swapping was first reported in 1994 for diphtheria toxin. Since then, 3D domain swapping has been observed in a variety of proteins.

     Our research group has shown that various metalloproteins, including heme proteins and a copper protein, can undergo 3D domain swapping (Figure 1).1-2 For example, it has been known for half a century that cytochrome (cyt) c forms polymers, but the polymerization mechanism remained unknown. We found by X-ray crystallographic and spectroscopic analyses that cyt c forms polymers by successive domain swapping, where the C-terminal helix is displaced from its original position in the monomer and cyt c loses its electron transfer function.3 We have also utilized 3D domain swapping to construct various heme protein assemblies, including nanorings, nanocages, a heterodimer with different active sites, and amyloid fibrils.4-7 Recently, we found that antibody light chains can undergo 3D domain swapping.8-9 This lecture will introduce basics and our recent developments of 3D domain swapping.

 

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Figure 1. Schematic representation of 3D domain swapping.

 

(1) Hirota, S. J. Inorg. Biochem. 2019, 194, 170-179 (review).

(2) Hirota, S.; Mashima, T.; Kobayashi, N. Chem. Commun. 2021, 57, 12074-12086 (review).

(3) Hirota, S.; Hattori, Y.; Nagao, S.; et al. Proc. Natl. Acad. Sci. USA 2010, 107, 12854-12859.

(4) Lin, Y.-W.; Nagao, S.; Zhang, M.; et al. Angew. Chem. Int. Ed. 2015, 54, 511-515.

(5) Miyamoto, T.; Kuribayashi, M.; Nagao, S.; et al. Chem. Sci. 2015, 6, 7336-7342.

(6) Yuyama, K.; Ueda, M.; Nagao, S.; et al. Angew. Chem. Int. Ed. 2017, 56, 6739-6743.

(7) Novientri, G.; Fujiwara, K.; Mashima, T.; et al. Eur. J. Chem., in press.

(8) Sakai, T.; Mashima, T.; Kobayashi, N.; et al. Nat. Commun. 2023, 14, 7807.

(9) Fitriana, W.; Sakai, T.; Duan, L.; et al. J. Med. Chem. 2024, 67, 22313-22321.