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Structural Insights into the Modulation of Synaptic Adhesion by MDGA for Synaptogenesis
Synapses connected by various synaptic adhesion molecules are communication spaces between neurons for transmitting information. Among various synaptic adhesion molecules, neuroligins are arguably the most widely studied class of postsynaptic adhesion molecules, which mainly interact with presynaptic neurexins to induce excitatory or inhibitory synapse development. Recently, the membrane-associated mucin (MAM) domain-containing GPI anchor protein 1 (MDGA1) has been characterized as a key suppressor of Neuroligin-2/Neurexin-1β-mediated inhibitory synapse development, but how it acts remains a mystery. In a recent issue of Neuron, published on June 21, 2017, a research team led by Professor Ho Min Kim at the Graduate School of Medical Science and Engineering of KAIST reported the three-dimensional structure of MDGA1/Neuroligin-2 complex and mechanistic insights into how MDGAs negatively modulate synapse development governed by Neurexins/Neuroligins trans -synaptic adhesion complex. MDGA1 consists of six Ig-like domains, fibronectin type III repeat domain, and MAM domain . The crystal structure of MDGA1/Neuroligin-2 complex reveals that they form the 2:2 hetero-tetrameric complex and only the Ig1-Ig2 domains of MDGA1 are involved in interactions with Neuroligin-2. The structural comparison between the MDGA1/Neuroligin-2 and Neurexin-1β/Neuroligin-1 complexes intriguingly indicates that the Neuroligin-2 region binding to MDGA1 largely overlaps with that of Neurexin-1β, but the interaction interface of the MDGA1/Neuroligin-2 complex is much larger than that of the Neurexin-1β/Neuroligin-1 complex. This explains why Neuroligin-2 binds stronger to MDGA1 than Neurexin-1β, and how the favored MDGA1 binding to Neuroligin-2 sterically blocks the interaction between Neuroligin-2 and Neurexin-1β, which is critical for the suppression of inhibitory synapse development. “Although we found that MDGA Ig domains (Ig 1 and Ig 2) are sufficient to form a complex with NL2, other extracellular domains, including Ig 3–6, FN III, and MAM domains, may also contribute to stable cis-interactions between MDGA1 and Neuroligin-2 by providing conformational flexibility. Therefore, further structural analysis of full-length MDGA will be required,” Professor Kim said. Neuroligin-2 specifically promotes the development of inhibitory synapses, whereas neuroligin-1 promotes the development of excitatory synapses. Recently, not only MDGA1, but also MDGA2 have emerged as synaptic regulators for the development of excitatory or inhibitory synapses. In vitro biochemical analysis in this research clearly demonstrates that Neuroligin-1 and Neuroligin-2 bind to both MDGA1 and MDGA2 with comparable affinity. However, pull-down assays using detergent-solubilized mouse brain membrane fractions show the specific interaction of MDGA1 with Neuroligin-2, but not with Neuroligin-1. “This suggests that unidentified processes may dictate the selective association of MDGA1 with Neuroligin-2 in vivo , ” explained Professor Jaewon Ko at the Daegu Gyeongbuk Institute of Science and Technology (DGIST). A balance between excitatory and inhibitory synapses is crucial to healthy cognition and behavior. Mutations in neuroligins, neurexins, and MDGAs, which can disrupt the excitatory/inhibitory balance, are associated with neuropsychiatric diseases such as autism and schizophrenia. Jung A Kim at KAIST, first author in this study, said, “Our discovery from integrative investigations are an important first step both for a better understanding of Neuroligin/Neurexin synaptic adhesion pathways and MDGA-mediated regulation of synapse development as well as the development of potential new therapies for autism, schizophrenia, and epilepsy.”
Dr. Sung-Chul Shin Selected 16th President of KAIST
(President Sung-Chul Shin) The KAIST Board of Trustees elected Professor Sung-Chul Shin of the Department of Physics the 16th president of KAIST on February 21. Professor Shin succeeds President Sung-Mo Kang whose four-year term will end on February 23. He is the first KAIST alumnus to serve as its president. The Board of Trustees announced, “We believe that Professor Shin’s scientific achievement, outstanding leadership, and clear vision will serve KAIST faculty, students, and staff very well. He will be the best person to help KAIST leap forward in the four years ahead.” The newly-elected president said, “I am humbled and honored to have been elected to lead such a prestigious institute of Korea. Aiming to be one of the top ten global universities, KAIST will continue to innovate its systems.” Previously, Dr. Shin led the Daegu Gyeongbuk Institute of Science and Technology (DGIST) for six years as president since 2011. Professor Shin joined the KAIST faculty in 1989. He graduated from Seoul National University and then earned his MS degree in condensed matter physics at KAIST in 1977. After earning his Ph.D. in material physics at Northwestern University in 1984, he worked at Eastman Kodak Research Labs as a senior research scientist for five years. Before heading to DGIST, President Shin held key administrative positions at KAIST from the early 1990s including dean of planning, dean of the international office, and vice-dean of student affairs. During President Robert Laughlin’s tenure, the first foreign president at KAIST, he served as vice-president for two years from 2004. He also served on the Presidential Advisory Council on Science and Technology of the Korean government as vice chairperson from 2015 to 2016. A renowned scholar in the field of nanoscience, President Shin’s research focuses on the artificial synthesis and characterization of nonmagnetic materials, magnetic anisotropy, and magneto-optical phenomena. He leads the Laboratory for Nanospinics of Spintronic Materials at KAIST and has published in 290 journals while holding 37 patents. A fellow in the American Physical Society (APS) since 2008, he was the president of the Korean Physical Society from 2011 to 2012. He has been on the editorial board of J. Magnetism and Magnetic Materials from 2009 and was the first Korean recipient of the Asian Union of Magnetics Societies (AUMS) Award, which recognizes outstanding scientists in the field of magnetics. President Shin envisions making KAIST’s research and education more competitive through continuing innovation. His innovation efforts will extend to the five key areas of education, research, technology commercialization, globalization, and future planning. Among his priorities, he emphasizes multidisciplinary studies and leadership training for students. He plans to focus on undeclared major courses for undergraduates to help them expand their experience and exposure to diverse disciplines. This approach will help create well-rounded engineers, scientists, and entrepreneurs by enabling them to develop skills while leveraging a strong connection to the arts, humanities, and social sciences. To better respond to Industry 4.0, which calls for convergence studies and collaborative work, he proposed establishing a ‘Convergence Innovation System’ by strategically selecting 10 flagship convergence research groups. In order to accelerate the technology commercialization and ecosystem of start-ups, he will strengthen entrepreneurship education, making it a prerequisite requirement for students. President Shin said he will spare no effort to incubate and spin-off ventures in which KAIST technology is being transferred. For globalization efforts, he plans to increase the ratio of foreign faculty from 9 percent to 15 percent, while doubling the current foreign student enrollment ratio of 5 percent. For future strategic innovation, he will implement a long-term innovation strategic plan dubbed ‘Vision 2031.’
JETS Conference 2017
KAIST and four science and technology research universities in Korea co-hosted a technology start-up fair, the 2017 JETS (Job, Exhibition, Tech Forum, and Startup) Conference January 19 ~20 in the Ryu Geun-chul Sports Complex at KAIST. Korea’s major science and technology research universities, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Gwangju Institute of Science and Technology (GIST), Pohang University of Science and Technology (Postech), and Ulsan National Institute of Science and Technology (UNIST), held the event in a collaborative effort to educate, inspire, and connect young entrepreneurs, especially those who will launch technology start-ups. The conference brought entrepreneurs and innovators together who seek ways of working with and supporting start-ups and for their sustainable growth. It also drew aspiring young students and researchers from universities and the government-funded research institutions who are in the process of commercializing their technology. Students from each university’s industry-academia cooperation program who incubated their technology and ideas were key contributors. At the Tech Forum, entrepreneurship and technology consultation specialists including Joe Jasin, managing director at DNA Investment Partners in the US, the founder of Cyworld Dong-Hyung Lee, and Professor Hawoong Jeong, a complex bio-network specialist from the Department of Physics of KAIST lectured on the ecosystem of start-ups and its trends and development. The Dean of University-Industry Cooperation at KAIST Joongmyeon Bae said, "We organized this event in collaboration with four major research universities to further encourage technology start-ups from young students and help their ideas and technology bear fruit. We will continue to strive to create an ecosystem of start-ups which works efficiently.” (Above photo: Founder of the Cyworld, Dong-Hyung Lee gives a lecture at the Tech Forum. Below photo: Students visit exhibition booth of each participating institution.)
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