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  1. Article ; Online: Membrane-Driven Dimerization of the Peripheral Membrane Protein KRAS: Implications for Downstream Signaling.

    Lee, Ki-Young

    International journal of molecular sciences

    2024  Volume 25, Issue 5

    Abstract: Transient homo-dimerization of the RAS GTPase at the plasma membrane has been shown to promote the mitogen-activated protein kinase (MAPK) signaling pathway essential for cell proliferation and oncogenesis. To date, numerous crystallographic studies have ...

    Abstract Transient homo-dimerization of the RAS GTPase at the plasma membrane has been shown to promote the mitogen-activated protein kinase (MAPK) signaling pathway essential for cell proliferation and oncogenesis. To date, numerous crystallographic studies have focused on the well-defined GTPase domains of RAS isoforms, which lack the disordered C-terminal membrane anchor, thus providing limited structural insight into membrane-bound RAS molecules. Recently, lipid-bilayer nanodisc platforms and paramagnetic relaxation enhancement (PRE) analyses have revealed several distinct structures of the membrane-anchored homodimers of KRAS, an isoform that is most frequently mutated in human cancers. The KRAS dimerization interface is highly plastic and altered by biologically relevant conditions, including oncogenic mutations, the nucleotide states of the protein, and the lipid composition. Notably, PRE-derived structures of KRAS homodimers on the membrane substantially differ in terms of the relative orientation of the protomers at an "α-α" dimer interface comprising two α4-α5 regions. This interface plasticity along with the altered orientations of KRAS on the membrane impact the accessibility of KRAS to downstream effectors and regulatory proteins. Further, nanodisc platforms used to drive KRAS dimerization can be used to screen potential anticancer drugs that target membrane-bound RAS dimers and probe their structural mechanism of action.
    MeSH term(s) Humans ; Proto-Oncogene Proteins p21(ras)/metabolism ; Dimerization ; Signal Transduction/genetics ; Lipid Bilayers ; Protein Isoforms/metabolism ; ras Proteins/metabolism ; Membrane Proteins/metabolism
    Chemical Substances Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Lipid Bilayers ; Protein Isoforms ; ras Proteins (EC 3.6.5.2) ; Membrane Proteins ; KRAS protein, human
    Language English
    Publishing date 2024-02-21
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms25052530
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  2. Article ; Online: Conditional Cooperativity in RAS Assembly Pathways on Nanodiscs and Altered GTPase Cycling.

    Lee, Soo-Yeon / Lee, Ki-Young

    Angewandte Chemie (International ed. in English)

    2024  Volume 63, Issue 13, Page(s) e202316942

    Abstract: Self-assemblies (i.e., nanoclusters) of the RAS GTPase on the membrane act as scaffolds that activate downstream RAF kinases and drive MAPK signaling for cell proliferation and tumorigenesis. However, the mechanistic details of nanoclustering remain ... ...

    Abstract Self-assemblies (i.e., nanoclusters) of the RAS GTPase on the membrane act as scaffolds that activate downstream RAF kinases and drive MAPK signaling for cell proliferation and tumorigenesis. However, the mechanistic details of nanoclustering remain largely unknown. Here, size-tunable nanodisc platforms and paramagnetic relaxation enhancement (PRE) analyses revealed the structural basis of the cooperative assembly processes of fully processed KRAS, mutated in a quarter of human cancers. The cooperativity is modulated by the mutation and nucleotide states of KRAS and the lipid composition of the membrane. Notably, the oncogenic mutants assemble in nonsequential pathways with two mutually cooperative 'α/α' and 'α/β' interfaces, while α/α dimerization of wild-type KRAS promotes the secondary α/β interaction sequentially. Mutation-based interface engineering was used to selectively trap the oligomeric intermediates of KRAS and probe their favorable interface interactions. Transiently exposed interfaces were available for the assembly. Real-time NMR demonstrated that higher-order oligomers retain higher numbers of active GTP-bound protomers in KRAS GTPase cycling. These data provide a deeper understanding of the nanocluster-enhanced signaling in response to the environment. Furthermore, our methodology is applicable to assemblies of many other membrane GTPases and lipid nanoparticle-based formulations of stable protein oligomers with enhanced cooperativity.
    MeSH term(s) Humans ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Signal Transduction ; ras Proteins/chemistry ; raf Kinases/metabolism ; Dimerization
    Chemical Substances Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2) ; raf Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2024-02-20
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.202316942
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  3. Article: Dynamics-Based Regulatory Switches of Type II Antitoxins: Insights into New Antimicrobial Discovery.

    Lee, Ki-Young / Lee, Bong-Jin

    Antibiotics (Basel, Switzerland)

    2023  Volume 12, Issue 4

    Abstract: Type II toxin-antitoxin (TA) modules are prevalent in prokaryotes and are involved in cell maintenance and survival under harsh environmental conditions, including nutrient deficiency, antibiotic treatment, and human immune responses. Typically, the type ...

    Abstract Type II toxin-antitoxin (TA) modules are prevalent in prokaryotes and are involved in cell maintenance and survival under harsh environmental conditions, including nutrient deficiency, antibiotic treatment, and human immune responses. Typically, the type II TA system consists of two protein components: a toxin that inhibits an essential cellular process and an antitoxin that neutralizes its toxicity. Antitoxins of type II TA modules typically contain the structured DNA-binding domain responsible for TA transcription repression and an intrinsically disordered region (IDR) at the C-terminus that directly binds to and neutralizes the toxin. Recently accumulated data have suggested that the antitoxin's IDRs exhibit variable degrees of preexisting helical conformations that stabilize upon binding to the corresponding toxin or operator DNA and function as a central hub in regulatory protein interaction networks of the type II TA system. However, the biological and pathogenic functions of the antitoxin's IDRs have not been well discussed compared with those of IDRs from the eukaryotic proteome. Here, we focus on the current state of knowledge about the versatile roles of IDRs of type II antitoxins in TA regulation and provide insights into the discovery of new antibiotic candidates that induce toxin activation/reactivation and cell death by modulating the regulatory dynamics or allostery of the antitoxin.
    Language English
    Publishing date 2023-03-23
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2681345-2
    ISSN 2079-6382
    ISSN 2079-6382
    DOI 10.3390/antibiotics12040637
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  4. Article ; Online: DNA binding reveals hidden interdomain allostery of a MazE antitoxin from Mycobacterium tuberculosis.

    Eun, Hyun-Jong / Lee, Soo-Yeon / Lee, Ki-Young

    Biochemical and biophysical research communications

    2024  Volume 710, Page(s) 149898

    Abstract: Type II toxin-antitoxin (TA) systems are ubiquitously distributed genetic elements in prokaryotes and are crucial for cell maintenance and survival under environmental stresses. The antitoxin is a modular protein consisting of the disordered C-terminal ... ...

    Abstract Type II toxin-antitoxin (TA) systems are ubiquitously distributed genetic elements in prokaryotes and are crucial for cell maintenance and survival under environmental stresses. The antitoxin is a modular protein consisting of the disordered C-terminal region that physically contacts and neutralizes the cognate toxin and the well-folded N-terminal DNA binding domain responsible for autorepression of TA transcription. However, how the two functional domains communicate is largely unknown. Herein, we determined the crystal structure of the N-terminal domain of the type II antitoxin MazE-mt10 from Mycobacterium tuberculosis, revealing a homodimer of the ribbon-helix-helix (RHH) fold with distinct DNA binding specificity. NMR studies demonstrated that full-length MazE-mt10 forms the helical and coiled states in equilibrium within the C-terminal region, and that helical propensity is allosterically enhanced by the N-terminal binding to the cognate operator DNA. This coil-to-helix transition may promote toxin binding/neutralization of MazE-mt10 and further stabilize the TA-DNA transcription repressor. This is supported by many crystal structures of type II TA complexes in which antitoxins form an α-helical structure at the TA interface. The hidden helical state of free MazE-mt10 in solution, favored by DNA binding, adds a new dimension to the regulatory mechanism of type II TA systems. Furthermore, complementary approaches using X-ray crystallography and NMR allow us to study the allosteric interdomain interplay of many other full-length antitoxins of type II TA systems.
    MeSH term(s) Mycobacterium tuberculosis/metabolism ; Antitoxins/chemistry ; Models, Molecular ; Transcription Factors/metabolism ; DNA/metabolism ; Bacterial Proteins/metabolism
    Chemical Substances Antitoxins ; Transcription Factors ; DNA (9007-49-2) ; Bacterial Proteins
    Language English
    Publishing date 2024-04-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 205723-2
    ISSN 1090-2104 ; 0006-291X ; 0006-291X
    ISSN (online) 1090-2104 ; 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2024.149898
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  5. Article: Editorial: Biomarkers and therapeutic strategies in acute lymphoblastic leukemia.

    Lee, Ki-Young / Maggi, Maristella / Scotti, Claudia

    Frontiers in cell and developmental biology

    2023  Volume 11, Page(s) 1211569

    Language English
    Publishing date 2023-05-17
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2023.1211569
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  6. Article: Requirement for ER-mitochondria Ca

    Lee, Jung Kwon / Rosales, Jesusa L / Lee, Ki-Young

    Frontiers in cell and developmental biology

    2023  Volume 11, Page(s) 1124164

    Abstract: Acute lymphoblastic leukemia (aLL) is a malignant cancer in the blood and bone marrow characterized by rapid expansion of lymphoblasts. It is a common pediatric cancer and the principal basis of cancer death in children. Previously, we reported that L- ... ...

    Abstract Acute lymphoblastic leukemia (aLL) is a malignant cancer in the blood and bone marrow characterized by rapid expansion of lymphoblasts. It is a common pediatric cancer and the principal basis of cancer death in children. Previously, we reported that L-asparaginase, a key component of acute lymphoblastic leukemia chemotherapy, causes IP3R-mediated ER Ca
    Language English
    Publishing date 2023-02-21
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2023.1124164
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  7. Article ; Online: The Self-Association of the KRAS4b Protein is Altered by Lipid-Bilayer Composition and Electrostatics.

    Lee, Ki-Young / Ikura, Mitsuhiko / Marshall, Christopher B

    Angewandte Chemie (International ed. in English)

    2023  Volume 62, Issue 18, Page(s) e202218698

    Abstract: KRAS is a peripheral membrane protein that regulates multiple signaling pathways, and is mutated in ≈30 % of cancers. Transient self-association of KRAS is essential for activation of the downstream effector RAF and oncogenicity. The presence of anionic ... ...

    Abstract KRAS is a peripheral membrane protein that regulates multiple signaling pathways, and is mutated in ≈30 % of cancers. Transient self-association of KRAS is essential for activation of the downstream effector RAF and oncogenicity. The presence of anionic phosphatidylserine (PS) lipids in the membrane was shown to promote KRAS self-assembly, however, the structural mechanisms remain elusive. Here, we employed nanodisc bilayers of defined lipid compositions, and probed the impact of PS concentration on KRAS self-association. Paramagnetic NMR experiments demonstrated the existence of two transient dimer conformations involving alternate electrostatic contacts between R135 and either D153 or E168 on the "α4/5-α4/5" interface, and revealed that lipid composition and salt modulate their dynamic equilibrium. These dimer interfaces were validated by charge-reversal mutants. This plasticity demonstrates how the dynamic KRAS dimerization interface responds to the environment, and likely extends to the assembly of other signaling complexes on the membrane.
    MeSH term(s) Lipid Bilayers/chemistry ; Static Electricity ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Proteins/metabolism ; Molecular Conformation
    Chemical Substances Lipid Bilayers ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Proteins
    Language English
    Publishing date 2023-03-27
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.202218698
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  8. Article ; Online: The Self‐Association of the KRAS4b Protein is Altered by Lipid‐Bilayer Composition and Electrostatics

    Lee, Ki‐Young / Ikura, Mitsuhiko / Marshall, Christopher B.

    Angewandte Chemie International Edition 2023 Apr. 24, v. 62, no. 18, p. e202218698

    2023  

    Abstract: KRAS is a peripheral membrane protein that regulates multiple signaling pathways, and is mutated in ≈30 % of cancers. Transient self‐association of KRAS is essential for activation of the downstream effector RAF and oncogenicity. The presence of anionic ... ...

    Abstract KRAS is a peripheral membrane protein that regulates multiple signaling pathways, and is mutated in ≈30 % of cancers. Transient self‐association of KRAS is essential for activation of the downstream effector RAF and oncogenicity. The presence of anionic phosphatidylserine (PS) lipids in the membrane was shown to promote KRAS self‐assembly, however, the structural mechanisms remain elusive. Here, we employed nanodisc bilayers of defined lipid compositions, and probed the impact of PS concentration on KRAS self‐association. Paramagnetic NMR experiments demonstrated the existence of two transient dimer conformations involving alternate electrostatic contacts between R135 and either D153 or E168 on the “α4/5‐α4/5” interface, and revealed that lipid composition and salt modulate their dynamic equilibrium. These dimer interfaces were validated by charge‐reversal mutants. This plasticity demonstrates how the dynamic KRAS dimerization interface responds to the environment, and likely extends to the assembly of other signaling complexes on the membrane.
    Keywords carcinogenicity ; dimerization ; lipid composition ; membrane proteins ; phosphatidylserines ; plasticity
    Language English
    Dates of publication 2023-0424
    Size p. e202218698
    Publishing place Wiley & Sons, Ltd.
    Document type Article ; Online
    Note JOURNAL ARTICLE
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.202218698
    Database NAL-Catalogue (AGRICOLA)

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  9. Article ; Online: CXCR5 and TLR4 signals synergistically enhance non-small cell lung cancer progression.

    Shin, Ji Hye / Kim, Mi-Jeong / Kim, Ji Young / Kang, Yeeun / Kim, Duk-Hwan / Jeong, Soo-Kyung / Chun, Eunyoung / Lee, Ki-Young

    Clinical and translational medicine

    2024  Volume 14, Issue 1, Page(s) e1547

    MeSH term(s) Humans ; Carcinoma, Non-Small-Cell Lung/genetics ; Lung Neoplasms/genetics ; Toll-Like Receptor 4/genetics ; Receptors, CXCR5
    Chemical Substances Toll-Like Receptor 4 ; CXCR5 protein, human ; Receptors, CXCR5 ; TLR4 protein, human
    Language English
    Publishing date 2024-01-18
    Publishing country United States
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 2697013-2
    ISSN 2001-1326 ; 2001-1326
    ISSN (online) 2001-1326
    ISSN 2001-1326
    DOI 10.1002/ctm2.1547
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  10. Book ; Online ; E-Book: Korean functional foods

    Park, Kun-Young / Kwon, Dae Young / Lee, Ki Won / Park, Sunmin

    composition, processing and health benefits

    (Functional foods and nutraceuticals series)

    2018  

    Author's details edited by Kun-Young Park, Dae Young Kwon, Ki Won Lee, Sunmin Park
    Series title Functional foods and nutraceuticals series
    Language English
    Size 1 Online-Ressource (564 Seiten)
    Publisher CRC
    Publishing place Boca Raton ; London ; New York
    Publishing country United States
    Document type Book ; Online ; E-Book
    Remark Zugriff für angemeldete ZB MED-Nutzerinnen und -Nutzer
    HBZ-ID HT019735169
    ISBN 978-1-351-64369-6 ; 978-1-4987-9966-9 ; 9781498799652 ; 1-351-64369-X ; 1-4987-9966-3 ; 1498799655
    Database ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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