Home Health Professor Kim Hak-seong’s team from the Department of Life Sciences at KAIST develops a technology for assembling giant protein structures like Lego blocks

Professor Kim Hak-seong’s team from the Department of Life Sciences at KAIST develops a technology for assembling giant protein structures like Lego blocks

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Professor Hakseong Kim [사진출처=카이스트]


[한국강사신문 장한별 기자] KAIST (President Lee Kwang-hyung) announced on the 19th that a team led by Professor Kim Hak-seong and Dr. Bae Jin-ho of the Department of Life Sciences has developed a new technology that can assemble large (supramolecular) proteins like Lego blocks.

In this way, the size and number of functional groups of the protein structure can be adjusted as desired, and a symmetrical large protein structure with a mega-dalton size can be assembled. The large protein structure is expected to be utilized for efficient drug delivery, development of various vaccines, and disease diagnosis.

The results of this research were published online on November 1, 2021 in ‘Advanced Science’ (IF: 16.806), an international renowned academic journal. (Paper title: Dendrimer-like supramolecular assembly of proteins with a tunable size and valency through stepwise iterative growth)

Proteins with very diverse properties and functions exist in the natural world and play a key role in maintaining life phenomena. Among these proteins, the monomer performs a normal function only when it is assembled into a large structure, or in some cases, when the monomer is assembled, it exhibits completely different characteristics from that of the monomer, and in many cases it even causes serious diseases.

Dr. Jinho Bae [사진출처=카이스트]
Dr. Jinho Bae [사진출처=카이스트]

For example, the cepseid, which is the shell of a virus, is an assembly of protein monomers, and dementia occurs when amyloid peptide or tau protein is assembled in the form of fibril. Therefore, understanding the assembly mechanism of macromolecular (supramolecular) protein structures is important for the identification of protein functions and causes of diseases and development of therapeutic agents. In addition, the protein construct has great potential for application in biotechnology and medicine because of its excellent biocompatibility.

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Currently, many research groups are conducting a lot of research on the development of protein structures with new functions by mimicking the assembly process of protein structures existing in nature. However, due to the structural diversity, different properties, and large molecular weight of proteins, it remains a difficult task to freely assemble a desired structure.

Professor Hakseong Kim’s research team has developed a method for assembling a three-dimensional symmetrical large protein structure simply by sequentially and alternately binding two types of building block proteins to a core protein (Figure 1). In other words, by sequentially and repeatedly binding two types of building blocks to a core protein using two pairs of proteins and ligands (P1/L1 and P2/L2) that specifically react with each other, size and action A protein construct having a mega Dalton size was easily assembled while controlling the number of mechanisms.

The developed structure can be applied to various fields, and as an example, in this study, a bacterial toxin was bound to a protein structure and delivered into the cancer cell with high efficiency, and as a result, the cancer cell was effectively killed (Figure 2). Due to the avidity effect, which is a characteristic of the structural protein, the binding force to the cancer target is increased by about 1,000 times or more, and the cancer cell killing effect has been dramatically increased, and this characteristic can be applied to vaccine development and disease diagnosis.

Dr. Bae Jin-ho, the first author, said, “The macro (supramolecular) protein structure assembly technology developed in this study can be used as a new platform technology in a wide range of fields, including drug delivery, vaccine development, disease diagnosis, and biosensors in the future. ‘ he said.

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This research was carried out with support from the National Research Foundation of Korea (NRF-2021R1A2C201421811).

Figure 1. Schematic diagram of sequential and alternating binding methods for assembling large proteins [사진출처=카이스트]
Figure 1. Schematic diagram of sequential and alternating binding methods for assembling large proteins [사진출처=카이스트]

<연구 배경>

Proteins with very diverse properties and functions exist in the natural world and play a key role in maintaining life phenomena. Among these proteins, only when the monomers are assembled into a large structure, they perform their normal functions or exhibit completely different characteristics from those of the monomers, and in many cases they cause serious diseases.

Therefore, understanding the assembly mechanism of large (supramolecular) protein structures is important for the identification of protein functions and causes of diseases and development of therapeutic agents. In addition, the protein construct has high potential for application in biotechnology and medicine because of its excellent biocompatibility. Currently, many research groups are conducting a lot of research on the development of protein structures with new functions by mimicking the assembly process of protein structures existing in nature.

Mainly, helical bundle interaction, peptide ligand interaction, disulfide bond formation, chemical bonding, metal ion interaction, magnetic binding protein fusion and methods through computer design have been tried. However, due to the structural diversity, different properties and large molecular weights of proteins, it remains a difficult task to freely assemble a desired structure.

[사진출처=카이스트]
Figure 2. Effect of efficient intracellular protein delivery of constructs [사진출처=카이스트]

<연구 내용>

By sequentially and alternately binding two types of building block proteins to the core protein, we developed a method to easily assemble a three-dimensional symmetrical large protein structure. That is, by sequentially and repeatedly binding two types of building blocks to the core protein using two pairs of proteins and ligands (P1/L1 and P2/L2) that specifically react with each other, while controlling the size and number of mechanisms of action, Protein constructs with mega Dalton size can be easily assembled.

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Specifically, starting from a small core protein with a size of 27 kDa, a large protein structure having a size of 959 kDa was finally produced through a total of four assembly steps.

In addition, since the binding value of the protein construct increases by a factor of 2 for each assembly step, the number of valencies of the construct can be easily controlled, and various proteins can be easily bound.

When a protein specific to the cancer-targeted epidermal growth factor receptor (EGFR) was bound to a protein construct, the binding force to EGFR was increased by more than 1,000 times that of the monomer due to the avidity effect, a characteristic of the construct protein.

When a bacterial toxin translocation domain, green fluorescent protein, and plant-derived toxin protein ‘gelonin’ were combined with a structure for efficient intracellular protein delivery through increased binding force, intracellular protein delivery was greatly increased. The cancer cell killing effect was confirmed.

<기대 효과>

The developed method for assembling large protein structures will contribute to understanding the mechanism of assembly and action of various structures existing in nature. In addition, the protein structure can easily control the size and avidity effect, can be functionalized with various protein cargo, and is composed only of proteins with high biocompatibility. Therefore, the large protein structure assembly technology is expected to be utilized as a platform technology in a wide range of fields including drug delivery, vaccine development, disease diagnosis, and biosensor in the future.

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