Department+of+Bio
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Binding Regulatory Mechanism of Protein Biomolecules Revealed
Professor Hak-Sung Kim
A research team led by Professor Hak-Sung Kim of Biological Sciences, KAIST, and Dr. Mun-Hyeong Seo, KAIST, has revealed a regulatory mechanism that controls the binding affinity of protein’s biomolecules, which is crucial for the protein to recognize molecules and carry out functions within the body.
The research results were published in the April 24th online edition of Nature Communications.
The protein, represented by enzyme, antibody, or hormones, specifically recognizes a variety of biomolecules in all organisms and implements signaling or immune response to precisely adjust and maintain important biological processes. The protein binding affinity of biomolecules plays a crucial role in determining the duration of the bond between two molecules, and hence to determine and control the in-vivo function of proteins.
The researchers have noted that, during the process of proteins’ recognizing biomolecules, the protein binding affinity of biomolecules is closely linked not only to the size of non-covalent interaction between two molecules, but also to the unique kinetic properties of proteins.
To identify the basic mechanism that determines the protein binding affinity of biomolecules, Professor Kim and his research team have made mutation in the allosteric site of protein to create a variety of mutant proteins with the same chemical binding surface, but with the binding affinity vastly differing from 10 to 100 times. The allosteric site of the protein refers to a region which does not directly bind with biomolecules, but crucially influences the biomolecule recognition site.
Using real-time analysis at the single-molecule level of unique kinetic properties of the produced mutant proteins, the researchers were able to identify that the protein binding affinity of biomolecules is directly associated with the protein’s specific kinetic characteristics, its structure opening rate.
Also, by proving that unique characteristics of the protein can be changed at the allosteric site, instead of protein’s direct binding site with biomolecules, the researchers have demonstrated a new methodology of regulating the in-vivo function of proteins.
The researchers expect that these results will contribute greatly to a deeper understanding of protein’s nature that governs various life phenomena and help evaluate the proof of interpreting protein binding affinity of biomolecules from the perspective of protein kinetics.
Professor Kim said, “Until now, the protein binding affinity of biomolecules was determined by a direct interaction between two molecules. Our research has identified an important fact that the structure opening rate of proteins also plays a crucial role in determining their binding affinity.”
[Picture]
A correlation graph of opening rate (kopening) and binding affinity (kd) between protein’s stable, open state and its unstable, partially closed state.
2014.05.02 View 11463 -
A Molecular Switch Controlling Self-Assembly of Protein Nanotubes Discovered
International collaborative research among South Korea, United States, and Israel research institutionsThe key to the treatment of cancer and brain disease mechanism The molecular switch that controls the self-assembly structure of the protein nanotubes, which plays crucial role in cell division and intracellular transport of materials, has been discovered. KAIST Bio and Brain Engineering Department’s Professor Myeong-Cheol Choi and Professor Chae-Yeon Song conducted the research, in collaboration with the University of California in Santa Barbara, U.S., and Hebrew University in Israel. The findings of the research were published in Nature Materials on the 19th. Microtubules are tube shaped and composed of protein that plays a key role in cell division, cytoskeleton, and intercellular material transport and is only 25nm in diameter (1/100,000 thickness of a human hair). Conventionally, cancer treatment focused on disrupting the formation of microtubules to suppress the division of cancer cells. In addition Alzheimer’s is known to be caused by the diminishing of structural integrity of microtubules responsible for intercellular material transport which leads to failure in signal transfer. The research team utilized synchrotron x-ray scattering and transmission electron microscope to analyze the self assemble structure of protein nanotubes to subnanometer accuracy. As a result, the microtubules were found to assemble into 25nm thickness tubules by stacking protein blocks 4 x 5 x 8nm in dimension. In the process, the research team discovered the molecular switch that controls the shape of these protein blocks. In addition the research team was successful in creating a new protein tube structure. Professor Choi commented that they were successful in introducing a new paradigm that suggests the possibility of controlling the complex biological functions of human’s biological system with the simple use of physical principles. He commented further that it is anticipated that the findings will allow for the application of bio nanotubes in engineering and that this is a small step in finding the mechanism behind cancer treatment and neural diseases.
2014.02.03 View 12278 -
Mechanism in regulation of cancer-related key enzyme, ATM, for DNA damage and repair revealed
Professor Kwang-Wook Choi
A research team led by Professor Kwang-Wook Choi and Dr. Seong-Tae Hong from the Department of Biological Sciences at KAIST has successfully investigated the operational mechanism of the protein Ataxia Telangiectasia Mutated (ATM), an essential protein to the function of a crucial key enzyme that repairs the damaged DNA which stores biometric information. The results were published on December 19th Nature Communications online edition.
All organisms, including humans, constantly strive to protect the information within their DNA from damages posed by a number of factors, such as carbonized materials in our daily food intake, radioactive materials such as radon emitting from the cement of buildings or ultraviolet of the sunlight, which could be a trigger for cancer.
In order to keep the DNA information safe, the organisms are always carrying out complex and sophisticated DNA repair work, which involves the crucial DNA damage repair protein ATM. Consequently, a faulty ATM leads to higher risks of cancer.
Until now, academia predicted that the Translationally Controlled Tumor Protein (TCTP) will play an important role in regulating the function of ATM. However, since most of main research regarding TCTP has only been conducted in cultured cells, it was unable to identify exactly what mechanisms TCTP employs to control ATM.
The KAIST research team identified that TCTP can combine with ATM or increase the enzymatic activity of ATM. In addition, Drosophilia, one of the most widely used model organisms for molecular genetics, has been used to identify that TCTP and ATM play a very important role in repairing the DNA damaged by radiation. This information has allowed the researchers to establish TCTP’s essential function in maintaining the DNA information in cell cultures and even in higher organisms, and to provide specific and important clues to the regulation of ATM by TCTP.
Professor Kwang-Wook Choi said, “Our research is a good example that basic research using Drosophilia can make important contributions to understanding the process of diseases, such as cancer, and to developing adequate treatment.”
The research has been funded by the Ministry of Science, ICT and Future Planning, Republic of Korea, and the National Research Foundation of Korea.
Figure 1. When the amount of TCTP protein is reduced, cells of the Drosophila's eye are abnormally deformed by radiation. Scale bars = 200mm
Figure 2. When the amount of TCTP protein is reduced, the chromosomes of Drosophilia are easily broken by radiation. Scale bars = 10 mm.
Figure 3. When gene expressions of TCTP and ATM are reduced, large defects occur in the normal development of the eye. (Left: normal Drosophilia's eye, right: development-deficient eye)
Figure 4. ATM marks the position of the broken DNA, with TCTP helping to facilitate this reaction. DNA (blue line) within the cell nucleus is coiled around the histone protein (green cylinder). When DNA is broken, ATM protein attaches a phosphate group (P). Multiple DNA repair protein recognizes the phosphate as a signal that requires repair and gathers at the site.
2014.01.07 View 16602 -
Opening Ceremony of Genetic Donguibogam held
- Medicine using traditional natural substances • Food product source technology development begins
- Over 150,000,000,000 Won for 10 years of work invested to develop source technology
- Opening ceremony held on November 26th at 3 p.m. in Bio & Brain Engineering Division Building
The research to develop medicine and food source technology using traditional natural substances hasbegun.The opening ceremony of the “Genetic Donguibogam” business group, with KAIST Department of Bio & Brain Engineering Professor Do Heon Lee as the leader, was held on November 26th at 3 p.m. in Dream Hall, Bio & Brain Engineering Division Building, KAIST, Daejeon. The attendees of the opening ceremony included Yo Eop Im, Head of the Future Technology Department of the Ministry of Science, ICT and Future Planning and around 200 experts in science and technology industry, including the National Research Foundation of Korea, KAIST, the Korea Institute of Science and Technology, Seoul National University and Yonsei University.
The business group was established to re-interpret traditional natural substances proved to be effective from experience and improve quality of life by researching its applications; and to develop integrated source technology using traditional natural substances. The group is to invest over 150,000,000,000 Won for 10 years of research to secure natural substance source technology in five stages: interpretation technology, analysis technology, verification technology, bio marker technology and human body effectiveness verification technology. Especially, the focus would be on the use of virtual body computer models and Omics* to analyse the effects of traditional natural substances mixture on human body, and to find new materials for healthcare.
This research model, it is hoped, will have a new item to pioneer in the world natural substance market as well as securing a technologically competitive edge in bio industry by developing source technology that investigates the effects of traditional natural substances using cutting edge science.
KAIST Department of Bio & Brain Engineering Professor and Head Do Heon Lee of the “Genetic Donguibogam” Business Group said, “We will push forward to develop source energy by integrating IT-BT technology with a computer virtual body to build a cooperation system with medicine and functional food industries.” He continued: “This will enable not only the creation of a new industry, but also customised medicine.”
The 12 partners of the group include KAIST, Korea Institute of Science and Technology, Seoul National University and Yonsei University and 200 experts. The research participation area will be widened to foreign research institutes and associated companies.
* Terminology
Noun) Omics is an academic discipline analysing mass information on metabolism of physiological phenomena in specific cells (transcriptome, proteome and protoplast) with an integrated approach to determine vital phenomena.
2013.12.11 View 11386 -
Two Dimensions of Value: Dopamine Neurons Represent Reward but not Aversiveness
Professor Christopher D. Fiorillo of the Bio & Brain Engineering (http://ineuron.kaist.ac.kr/web/home.html) at KAIST published a research paper in the August 2 issue of Science. The title of the paper is “Two Dimensions of Value: Dopamine Neurons Represent Reward but not Aversiveness.” The following is an introduction of his research work:
To make decisions, we need to estimate the value of sensory stimuli and motor actions, their “goodness” and “badness.” We can imagine that good and bad are two ends of a single continuum, or dimension, of value. This would be analogous to the single dimension of light intensity, which ranges from dark on one end to bright light on the other, with many shades of gray in between. Past models of behavior and learning have been based on a single continuum of value, and it has been proposed that a particular group of neurons (brain cells) that use dopamine as a neurotransmitter (chemical messenger) represent the single dimension of value, signaling both good and bad.
The experiments reported here show that dopamine neurons are sensitive to the value of reward but not punishment (like the aversiveness of a bitter taste). This demonstrates that reward and aversiveness are represented as two discrete dimensions (or categories) in the brain. “Reward” refers to the category of good things (food, water, sex, money, etc.), and “punishment” to the category of bad things (stimuli associated with harm to the body and that cause pain or other unpleasant sensations or emotions).
Rather than having one neurotransmitter (dopamine) to represent a single dimension of value, the present results imply the existence of four neurotransmitters to represent two dimensions of value. Dopamine signals evidence for reward (“gains”) and some other neurotransmitter presumably signals evidence against reward (“losses”). Likewise, there should be a neurotransmitter for evidence of danger and another for evidence of safety. It is interesting that there are three other neurotransmitters that are analogous to dopamine in many respects (serotonin, norepinephrine, and acetylcholine), and it is possible that they could represent the other three value signals.
For the research article, please visit: http://www.sciencemag.org/content/341/6145/546.abstract
For the Science 2nd issue, please visit: http://www.sciencemag.org/content/current#ResearchArticles
Illustration of Value Dimension
2013.08.08 View 9629 -
New Structural Insight into Neurodegenerative Disease
A research team from the Korea Advanced Institute of Science and Technology (KAIST) released their results on the structure and molecular details of the neurodegenerative disease-associated protein Ataxin-1. Mutations in Ataxin-1 cause the neurological disease, Spinocerebella Ataxia Type 1 (SCA1), which is characterized by a loss of muscular coordination and balance (ataxia), as is seen in Parkinson’s, Alzheimer’s, and Huntington’s diseases.
SCA1-causing mutations in the ATAXIN1 gene alter the length of a glutamine stretch in the Ataxin-1 protein. The research team provides the first structural insight into the complex formation of ATAXIN-1 with its binding partner, Capicua (CIC). The team, led by Professor Ji-Joon Song from the Department of Biological Sciences at KAIST, solved the structure of Ataxin-1 and CIC complex in atomic level revealing molecular details of the interaction between Ataxin-1 and CIC.
Professor Song explained his recent research work,
“We are able to see the intricate process of complex formation and reconfiguration of the two proteins when they interact with each other. Our work, we expect, will provide a new therapeutic target to modulate SCA1 neurodegenerative disease.”
Understanding structural and molecular details of proteins at the atomic level will help researchers to track the molecular pathogenesis of the disease and, ultimately, design targeted therapies or treatments for patients, rather than just relieving the symptoms of diseases.
Professor Song’s research paper, entitled “Structural Basis of Protein Complex Formation and Reconfiguration by Polyglutamine Disease Protein ATAXIN-1 and Capicua,” will be published in the March 15th issue of Genes & Development (www.genesdev.org).
Complex Formation and Reconfiguration of ATAXIN-1 and Capicua
The complex formation between a polyglutamine disease protein, ATXIN-1 and the transcriptional repressor Capicua (CIC) plays a critical role in SCA 1 pathogenesis. The image shows that the homodimerization of ATXIN-1 (yellow and red) is disrupted upon binding of CIC (blue). Furthermore, the binding of CIC to the ATXIN-1 induces a new form of ATXIN-1 dimerization mediated by CICs (ATXIN-1 AXH domains are shown in yellow and red, and CIC peptides shown in blue and white).
2013.04.02 View 10893 -
Ligand Recognition Mechanism of Protein Identified
Professor Hak-Sung Kim
-“Solved the 50 year old mystery of how protein recognises and binds to ligands”
- Exciting potential for understanding life phenomena and the further development of highly effective therapeutic agent development
KAIST’s Biological Science Department’s Professor Hak-Sung Kim, working in collaboration with Professor Sung-Chul Hong of Department of Physics, Seoul National University, has identified the mechanism of how the protein recognizes and binds to ligands within the human body.
The research findings were published in the online edition of Nature Chemical Biology (March 18), which is the most prestigious journal in the field of life science.
Since the research identified the mechanism, of which protein recognises and binds to ligands, it will take an essential role in understanding complex life phenomenon by understanding regulatory function of protein.
Also, ligand recognition of proteins is closely related to the cause of various diseases. Therefore the research team hopes to contribute to the development of highly effective treatments.
Ligands, well-known examples include nucleic acid and proteins, form the structure of an organism or are essential constituents with special functions such as information signalling.
In particular, the most important role of protein is recognising and binding to a particular ligand and hence regulating and maintaining life phenomena. The abnormal occurrence of an error in recognition of ligands may lead to various diseases.
The research team focused on the repetition of change in protein structure from the most stable “open form” to a relatively unstable “partially closed form”.
Professor Kim’s team analysed the change in protein structure when binding to a ligand on a molecular level in real time to explain the ligand recognition mechanism.
The research findings showed that ligands prefer the most stable protein structure. The team was the first in the world to identify that ligands alter protein structure to the most stable, the lowest energy level, when it binds to the protein.
In addition, the team found that ligands bind to unstable partially-closed forms to change protein structure.
The existing models to explain ligand recognition mechanism of protein are “Induced Custom Model”, which involves change in protein structure in binding to ligands, and the “Structure Selection Model”, which argues that ligands select and recognise only the best protein structure out of many. The academic world considers that the team’s research findings have perfectly proved the models through experiments for the first time in the world.
Professor Kim explained, “In the presence of ligands, there exists a phenomenon where the speed of altering protein structure is changed. This phenomenon is analysed on a molecular level to prove ligand recognition mechanism of protein for the first time”. He also said, “The 50-year old mystery, that existed only as a hypothesis on biology textbooks and was thought never to be solved, has been confirmed through experiments for the first time.”
Figure 1: Proteins, with open and partially open form, recognising and binding to ligands.
Figure 2: Ligands temporarily bind to a stable protein structure, open form, which changes into the most stable structure, closed form. In addition, binding to partially closed form also changes protein structure to closed form.
2013.04.01 View 14385 -
Novel material that prevents health decline with age found
Professor Kim Dae Soo (Department of Biological Science), his research team, the Choong Nam University Medicine School, and various companies conducted collaborative research succeeded in developing a novel material that prevents health decline with age. The result was published in PLoS One Journal with the title “Beta-lapachone, a modulator of NAD metabolism, prevents health declines in aged mice”.
Longevity and health can be obtained with reducing consumption of food and aerobic exercise.
Professor Kim’s team focused on the fact that reduced consumption of food and aerobic exercise increase the coenzyme (NAD+) which suppresses the aging of cells. The research team discovered that by activating NQO1 enzyme with Beta-lapachone, the amount of NAD+ in the body increases even without reduction of food consumption or aerobic exercise.
Even consumption of Beta-lapachone by aging mice caused an improved on the brain and exercise ability of the mice. It is expected that commercialization of Beta-lapachone will be possible as it is a chemical that is commonly found in herbs used in both the orient and the oxidant.
2012.12.21 View 8815
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Firefly inspired high efficiency LED technology developed
A firefly inspired, high efficiency self-illuminating LED has been developed.
Professor Jeong Gi Hoon (Department of Bio and Brain Engineering) mimicked the nanostructure of the external layer of the illumination organ of a firefly and succeeded in fabricating high illumination efficiency LED lenses.
Conventional lenses required expensive anti-reflection coating. The developed lenses utilize the bio-inspired nanostructure on the surface of the lenses themselves to reduce the reflectivity of the lenses thereby decreasing production costs.
The developed antireflection nanostructure is expected to be applied to various digital devices and lighting fixtures.
Antireflective structures have been applied in various fields in order to enhance light efficiency However these structures have been limited to flat surfaces and therefore was difficult to implement to curved surfaces like LED lenses.
Professor Jeong’s team solved this problem by using three dimensional micro molding processes.
The team fabricated the nanostructure by forming a single nanoparticle layer on the silicon oxide and performing dry etching. On this nanostructure PDMS was poured and manipulated to fabricate a lens structure similar to that of a firefly.
The fabricated lens showed similar efficiency as conventional antireflection coating.
2012.11.29 View 9962
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Liver Damage Mechanism of Hepatitis C Proven
KAIST researchers found mechanics behind a Hepatitis C virus, thereby taking a step closer to the development of a cure for Hepatitis C.
Professor Choi Chul Hui (Department of Biological and Brain Engineering) and Professor Shin Eui Chul (Graduate School of Medical Sciences) proved, for the first time in the world, the mechanism behind liver damage of a patient with Hepatitis C.
It is anticipated that this discovery will allow for the development of a Hepatitis C cure that has no side effects and little Liver damage.
Hepatitis C is an immune response of the body to the Hepatitis C virus and causes liver irritation.
Around 170million people are infected with Hepatitis C worldwide including 1% of the Korean population. Once infected, most cases turn into chronic cases and may lead to liver cancer.
However it was impossible to infect Hepatitis C within a test tube cell environment until 2005 and up till then Chimpanzees were used to study the virus which proved to be a huge barrier to research.
The research team used cells infected with Hepatitis C virus and found out that the virus works by increasing the destruction of cells by the TNF-a protein responsible for the cell’s immune response.
In addition the protein structure of the virus that causes this reaction was successfully found.
Conventionally the Hepatitis C medication focused on the suppressing the growth of the virus and therefore had many side effects.
The experimental results allow new medication aimed at suppressing the actual mechanism of liver damage to be discovered.
The result was selected as the cover dissertation of the September Edition of the Hepatolog magazine.
2012.09.11 View 15421
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Systems biology demystifies the resistance mechanism of targeted cancer medication
Korean researchers have found the fundamental resistance mechanism of the MEK inhibitor, a recently highlighted chemotherapy method, laying the foundation for future research on overcoming cancer drug resistance and improving cancer survival rates. This research is meaningful because it was conducted through systems biology, a fusion of IT and biotechnology.
The research was conducted by Professor Gwang hyun Cho’s team from the Department of Biology at KAIST and was supported by the Ministry of Education, Science and Technology and the National Research Foundation of Korea.
The research was published as the cover paper for the June edition of the Journal of Molecular Cell Biology (Title: The cross regulation between ERK and PI3K signaling pathways determines the tumoricidal efficacy of MEK inhibitor).
Targeted anticancer medication targets certain molecules in the signaling pathway of the tumor cell and not only has fewer side effects than pre-existing anticancer medication, but also has high clinical efficacy. The technology also allows the creation of personalized medication and has been widely praised by scientists worldwide.
However, resistances to the targeted medication have often been found before or during the clinical stage, eventually causing the medications to fail to reach the drug development stage. Moreover, even if the drug is effective, the survival rate is low and the redevelopment rate is high.
An active pathway in most tumor cells is the ERK (Extracellular signal-regulated kinases) signaling pathway. This pathway is especially important in the development of skin cancer or thyroid cancer, which are developed by the mutation of the BRAF gene inside the path. In these cases, the MEK (Extracellular signal-regulated kinases) inhibitor is an effective treatment because it targets the pathway itself. However, the built-up resistance to the inhibitor commonly leads to the redevelopment of cancer.
Professor Cho’s research team used large scale computer simulations to analyze the fundamental resistance mechanism of the MEK inhibitor and used molecular cell biological experiments as well as bio-imaging* techniques to verify the results.
* Bio-imaging: Checking biological phenomena at the cellular and molecular levels using imagery
The research team used different mutational variables, which revealed that the use of the MEK inhibitor reduced the transmission of the ERK signal but led to the activation of another signaling pathway (the PI3K signaling pathway), reducing the effectiveness of the medication. Professor Cho’s team also found that this response originated from the complex interaction between the signaling matter as well as the feedback network structure, suggesting that the mix of the MEK inhibitor with other drugs could improve the effects of the targeted anticancer medication.
Professor Cho stated that this research was the first of its kind to examine the drug resistivity against the MEK inhibitor at the systematic dimension and showed how the effects of drugs on the signaling pathways of cells could be predicted using computer simulation. It also showed how basic research on signaling networks can be applied to clinical drug use, successfully suggesting a new research platform on overcoming resistance to targeting medication using its fundamental mechanism.
2012.07.06 View 14382
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The hereditary factor of autism revealed
Korean researchers have successfully investigated the causes and hereditary factors for autistic behavior and proposed a new treatment method with fewer side effects.
This research was jointly supported by the Ministry of Education, Science and Technology and the National Research Foundation as part of the Leading Researcher and Science Research Center Program
The research findings were publishing in the June edition of Nature magazine and will also be introduced in the July edition of Nature Reviews Drug Discovery, under the title ‘Autistic-like social behavior in Shank2-mutant mice improved by restoring NMDA receptor function’.
The research team found that lack of Shank2 genes in mice, which are responsible for the production of synapse proteins, caused autistic-like behavior. The results strongly suggested that the Shank2 gene was linked to autistic behavior and that Shank2 deficiency induced autistic behaviors.
Autism is a neural development disorder characterized by impaired social interaction, repetitive behavior, mental retardation, anxiety and hyperactivity. Around 100 million people worldwide display symptoms of autistic behavior. Recent studies conducted by the University of Washington revealed that 1 out of 3 young adults who display autistic behavior do not fit into the workplace or get accepted to college, a much higher rate than any other disorder. However, an effective cure has not yet been developed and current treatments are limited to reducing repetitive behavior.
The research team confirmed autistic-like social behavior in mice without the Shank2 genes and that the mice had decreased levels of neurotransmission in the NMDA receptor. The mice also showed damaged synaptic plasticity* in the hippocampus**.
* Plasticity: ability of the connectionbetween two neurons to change in strength in response to transmission of information
**Hippocampus: part of the brain responsible for short-term and long-term memory as well as spatial navigation.
The research team also found out that, to restore the function of the NMDA receptor, the passive stimulation of certain receptors, such as the mGLuR5, yielded better treatment results than the direct stimulation of the NMDA. This greatly reduces the side effects associated with the direct stimulation of receptors, resulting in a more effective treatment method.
This research successfully investigated the function of the Shank2 gene in the nerve tissue and showed how the reduced function of the NMDA receptor, due to the lack of the gene, resulted in autistic behavior. It also provided new possibilities for the treatment of autistic behavior and impaired social interaction
2012.06.24 View 15432