Changwook Lee

Ulsan National Institute of Science and Technology

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Youngsoo Jun

Gwangju Institute of Science and Technology

Hanbin Jeong

Vollum Institute

Jumi Park

Ulsan National Institute of Science and Technology

Hakbong Lee

Ulsan National Institute of Science and Technology

Byoung Heon Kang

Ulsan National Institute of Science and Technology

Hyun‐Woo Rhee

Seoul National University

Soosung Kang

Ewha Womans University

Ji Hoon Lee

Daegu-Gyeongbuk Medical Innovation Foundation

Kyungjae Myung

Institute for Basic Science

Ki Bum Hong

Daegu-Gyeongbuk Medical Innovation Foundation

Cooperative Institutions

Inserm

149

Centre National de la Recherche Scientifique

134

University of Michigan–Ann Arbor

127

Harvard University

121

Chinese Academy of Sciences

National Institutes of Health

Istituti di Ricovero e Cura a Carattere Scientifico

Ulsan National Institute of Science and Technology

Consejo Superior de Investigaciones Científicas

Johns Hopkins University

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Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models

Bioorganic Chemistry (2020)

Darong Kim So-Yeon Kim Dongyoung Kim Nam Gu Yoon Jisu Yun

Geldanamycin

10.1016/j.bioorg.2020.103901

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Citations (17)

Ergosterol interacts with Sey1p to promote atlastin‐mediated endoplasmic reticulum membrane fusion inSaccharomyces cerevisiae

The FASEB Journal (2018)

Miriam Lee Yeojin Moon Sang-Hwa Lee Changwook Lee Youngsoo Jun

Sterols play critical roles in various membrane fusion events, including soluble NSF attachment protein receptor-mediated membrane fusion, mainly by modulating the physical properties of biologic membranes; however, it remains unclear whether they also function in atlastin-mediated endoplasmic reticulum (ER) membrane fusion. Although ergosterol, the major sterol in yeast, is essential for fusion of Sey1p (yeast atlastin)-containing liposomes with an ER-mimicking lipid composition, fusion of phosphatidylcholine/phosphatidylserine liposomes does not require sterols. Here, we examined whether sterols are important for Sey1p-mediated ER fusion in Saccharomyces cerevisiae using an in vitro ER fusion assay with isolated yeast ER microsomes. Ergosterol-specific ligands inhibited microsome fusion, indicating that ergosterol is critical for ER fusion. However, microsomes isolated from yeast strains lacking genes that encode enzymes involved in synthesis of ergosterol from lanosterol still fused, suggesting that other sterols can replace ergosterol and support Sey1p-mediated ER fusion. Importantly, disruption of sterol-binding motifs in the transmembrane regions of Sey1p markedly reduced ER fusion. Sey1p physically interacted with Erg11p and Erg4p, which function in ergosterol biosynthesis, suggesting that Sey1p recruits ergosterol-synthesizing enzymes to fusion sites and thereby enriches ergosterol, which, in turn, may recruit more Sey1p. This positive feedback loop may facilitate ER membrane fusion by concentrating fusion factors at fusion sites.—Lee, M., Moon, Y., Lee, S., Lee, C., Jun, Y. Ergosterol interacts with Sey1p to promote atlastin-mediated endoplasmic reticulum membrane fusion in Saccharomyces cerevisiae. FASEB J. 33, 3590–3600 (2019). www.fasebj.org

Ergosterol

10.1096/fj.201800779rr

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Rare Variants of Putative Candidate Genes Associated With Sporadic Meniere's Disease in East Asian Population

Frontiers in Neurology (2020)

Eun Hye Oh Jin‐Hong Shin Hyang-Sook Kim Jae Wook Cho Seo‐Young Choi

Objectives: The cause of Meniere's disease (MD) is unclear but likely involves genetic and environmental factors. The aim of this study was to investigate the genetic basis underlying MD by screening putative candidate genes for MD. Methods: Sixty-eight patients who met the diagnostic criteria for MD of the Barany Society were included. We performed targeted gene sequencing using next generation sequencing (NGS) panel composed of 45 MD-associated genes. We identified the rare variants causing non-synonymous amino acid changes, stop codons, and insertions/deletions in the coding regions, and excluded the common variants with minor allele frequency > 0.01 in public databases. The pathogenicity of the identified variants was analyzed by various predictive tools and protein structural modeling. Results: The average read depth for the targeted regions was 1446.3 fold, and 99.4% of the targeted regions were covered by 20 or more reads, achieving the high quality of the sequencing. After variant filtering, annotation, and interpretation, we identified a total of 15 rare heterozygous variants in 12 (17.6%) sporadic patients. Among them, four variants were detected in familial MD genes (DTNA, FAM136A, DPT), and the remaining 11 in MD-associated genes (PTPN22, NFKB1, CXCL10, TLR2, MTHFR, SLC44A2, NOS3, NOTCH2). Three patients had the variants in two or more genes. All variants were not detected in our healthy controls (n=100). No significant differences were observed between patients with and without a genetic variant in terms of sex, mean age of onset, bilaterality, the type of MD, and hearing threshold at diagnosis. Conclusions: Our study identified rare variants of putative candidate genes in some of MD patients. The genes were related to the formation of inner ear structures, the immune-associated process, or systemic hemostasis derangement, suggesting the multiple genetic predispositions in the development of MD.

Candidate gene

Founder effect

Minor allele frequency

Sanger sequencing

10.3389/fneur.2019.01424

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Citations (21)

Structural basis for inhibition of the replication licensing factor Cdt1 by geminin

Nature (2004)

Changwook Lee Bum‐Soo Hong Jung Min Choi Yugene Kim Saori Watanabe

10.1038/nature02813

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Citations (147)

Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site

Journal of the American Chemical Society (2021)

Nam Gu Yoon Hakbong Lee So-Yeon Kim S Hu Darong Kim

Heat shock protein 90 (Hsp90) family proteins are molecular chaperones that modulate the functions of various substrate proteins (clients) implicated in pro-tumorigenic pathways. In this study, the mitochondria-targeted antioxidant mitoquinone (MitoQ) was identified as a potent inhibitor of mitochondrial Hsp90, known as a tumor necrosis factor receptor-associated protein 1 (TRAP1). Structural analyses revealed an asymmetric bipartite interaction between MitoQ and the previously unrecognized drug binding sites located in the middle domain of TRAP1, believed to be a client binding region. MitoQ effectively competed with TRAP1 clients, and MitoQ treatment facilitated the identification of 103 TRAP1-interacting mitochondrial proteins in cancer cells. MitoQ and its redox-crippled SB-U014/SB-U015 exhibited more potent anticancer activity in vitro and in vivo than previously reported mitochondria-targeted TRAP1 inhibitors. The findings indicate that targeting the client binding site of Hsp90 family proteins offers a novel strategy for the development of potent anticancer drugs.

Chaperone (clinical)

Blocking (statistics)

10.1021/jacs.1c07099

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Citations (17)

Crystal structure of Mdm12 reveals the architecture and dynamic organization of the ERMES complex

EMBO Reports (2016)

Hanbin Jeong Jumi Park Changwook Lee

10.15252/embr.201642706

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Citations (73)

Genotype and Phenotype Spectrum ofFRMD7-Associated Infantile Nystagmus Syndrome

Investigative Ophthalmology & Visual Science (2018)

Jae‐Hwan Choi Jae Ho Jung Eun Hye Oh Jin‐Hong Shin Hyang-Sook Kim

Purpose: We investigate the genotype and phenotype spectrum of FRMD7-associated infantile nystagmus syndrome in Korean probands. Methods: A total of 37 patients with infantile nystagmus syndrome were recruited prospectively for genetic analysis. We performed polymerase chain reaction (PCR)-based direct sequencing and haplotype analysis for FRMD7. Detailed ophthalmic examinations and eye movement recordings were compared between FRMD7 and non-FRMD7 groups. Results: In 13 (35%) of 37 patients, five different mutations of FRMD7 were detected: start codon mutation c.1A>G, splice site mutation c.162+6T>C, and three missense mutations (c.575A>C, c.722A>G, and c.875T>C). The latter mutation was identified in seven unrelated patients, and always was accompanied with two single nucleotide polymorphisms of exon 12 (rs6637934, rs5977623). Compared to non-FRMD7 groups, a cup-to-disc ratio was significantly decreased in FRMD7 groups (P < 0.001), and a disc–macula distance to disc diameter ratio markedly increased in the FRMD7 group (P = 0.015). Most patients in the FRMD7 group had at least two types of the nystagmus waveforms, and the most common type was unidirectional jerk nystagmus (75%), such as pure jerk and jerk with extended foveation, followed by pendular (25%), bidirectional jerk (19%), and dual jerk (6%) nystagmus. No significant differences were observed between FRMD7 and non-FRMD7 groups in terms of the nystagmus waveform, presence of periodic alternating nystagmus, and mean foveation time. Conclusions: We identified five FRMD7 mutations in 35% of our infantile nystagmus syndrome cohort, expanding its mutational spectrum. The missense mutation c.875T>C may be a common mutation arisen from the founder effect in Korea. Optic nerve dysplasia associated with FRMD7 mutations suggests that the abnormal development of afferent visual systems may affect neural circuitry within the oculomotor system.

Proband

Jerk

10.1167/iovs.18-24207

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Citations (21)

Correction to “Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site”

Journal of the American Chemical Society (2022)

Nam Gu Yoon Hakbong Lee So-Yeon Kim S Hu Darong Kim

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to "Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site"Nam Gu YoonNam Gu YoonMore by Nam Gu Yoonhttps://orcid.org/0000-0002-5816-5508, Hakbong LeeHakbong LeeMore by Hakbong Leehttps://orcid.org/0000-0003-3260-6261, So-Yeon KimSo-Yeon KimMore by So-Yeon Kimhttps://orcid.org/0000-0003-1566-5438, Sung HuSung HuMore by Sung Huhttps://orcid.org/0000-0002-4920-0623, Darong KimDarong KimMore by Darong Kimhttps://orcid.org/0000-0002-9480-2981, Sujae YangSujae YangMore by Sujae Yang, Ki Bum HongKi Bum HongMore by Ki Bum Honghttps://orcid.org/0000-0002-4853-2263, Ji Hoon LeeJi Hoon LeeMore by Ji Hoon Leehttps://orcid.org/0000-0002-8118-861X, Soosung KangSoosung KangMore by Soosung Kanghttps://orcid.org/0000-0001-7016-2417, Byung-Gyu KimByung-Gyu KimMore by Byung-Gyu Kim, Kyungjae MyungKyungjae MyungMore by Kyungjae Myung, Changwook Lee*Changwook LeeMore by Changwook Leehttps://orcid.org/0000-0002-3016-9478, and Byoung Heon Kang*Byoung Heon KangMore by Byoung Heon Kanghttps://orcid.org/0000-0001-5902-0549Cite this: J. Am. Chem. Soc. 2022, 144, 4, 2020Publication Date (Web):January 19, 2022Publication History Published online19 January 2022Published inissue 2 February 2022https://pubs.acs.org/doi/10.1021/jacs.2c00039https://doi.org/10.1021/jacs.2c00039correctionACS PublicationsCopyright © 2022 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1602Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (473 KB) Get e-Alertsclose Get e-Alerts

10.1021/jacs.2c00039

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Citations (2)

Proximity-Directed Labeling Reveals a New Rapamycin-Induced Heterodimer of FKBP25 and FRB in Live Cells

ACS Central Science (2016)

Song-Yi Lee Hakbong Lee Hye-Kyeong Lee Seung-Won Lee Sung Chul Ha

Mammalian target of rapamycin (mTOR) signaling is a core pathway in cellular metabolism, and control of the mTOR pathway by rapamycin shows potential for the treatment of metabolic diseases. In this study, we employed a new proximity biotin-labeling method using promiscuous biotin ligase (pBirA) to identify unknown elements in the rapamycin-induced interactome on the FK506-rapamycin binding (FRB) domain in living cells. FKBP25 showed the strongest biotin labeling by FRB–pBirA in the presence of rapamycin. Immunoprecipitation and immunofluorescence experiments confirmed that endogenous FKBP25 has a rapamycin-induced physical interaction with the FRB domain. Furthermore, the crystal structure of the ternary complex of FRB–rapamycin–FKBP25 was determined at 1.67-Å resolution. In this crystal structure we found that the conformational changes of FRB generate a hole where there is a methionine-rich space, and covalent metalloid coordination was observed at C2085 of FRB located at the bottom of the hole. Our results imply that FKBP25 might have a unique physiological role related to metallomics in mTOR signaling.

Immunoprecipitation

Ternary complex

10.1021/acscentsci.6b00137

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Citations (44)

Crystallization and preliminary X-ray diffraction analysis of the Sel1-like repeats of SEL1L

Acta Crystallographica Section F Structural Biology Communications (2014)

Hanbin Jeong Hakbong Lee Changwook Lee

Terminally misfolded or unassembled proteins are selectively recognized and cleared by the ER-associated degradation (ERAD) pathway. Suppressor/enhancer of lin-12-like (SEL1L), a component of the dislocation machinery containing the E3 ubiquitin ligase Hrd1, plays an important role in selecting and transporting ERAD substrates for degradation in the endoplasmic reticulum. In this study, the purification, crystallization and preliminary X-ray diffraction analysis of recombinant mouse SEL1L (residues 348-533) are reported. The crystals were obtained by the hanging-drop vapour-diffusion method at pH 8.5 and 277 K using 30% 2-propanol as a precipitant. Optimized crystals diffracted to 3.3 Å resolution at a synchrotron-radiation source. Preliminary X-ray diffraction analysis revealed that the crystals belonged to space group P21 and contained four molecules per asymmetric unit, with a solvent content of 44%.

10.1107/s2053230x14023115

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Citations (1)