Pro-metastatic collagen lysyl hydroxylase dimer assemblies stabilized by Fe2+-binding

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dc.citation.articleNumber512en_US
dc.citation.journalTitleNature Communicationsen_US
dc.citation.volumeNumber9en_US
dc.contributor.authorGuo, Hou-Fuen_US
dc.contributor.authorTsai, Chi-Linen_US
dc.contributor.authorTerajima, Masahikoen_US
dc.contributor.authorTan, Xiaochaoen_US
dc.contributor.authorBanerjee, Priyamen_US
dc.contributor.authorMiller, Mitchell D.en_US
dc.contributor.authorLiu, Xinen_US
dc.contributor.authorYu, Jiangen_US
dc.contributor.authorByemerwa, Jovitaen_US
dc.contributor.authorAlvarado, Sarah K.en_US
dc.contributor.authorKaoud, Tamer S.en_US
dc.contributor.authorDalby, Kevin N.en_US
dc.contributor.authorBota-Rabassedas, Neusen_US
dc.contributor.authorChen, Yulongen_US
dc.contributor.authorYamauchi, Mitsuoen_US
dc.contributor.authorTainer, John A.en_US
dc.contributor.authorPhillips, George N.Jr.en_US
dc.contributor.authorKurie, Jonathan M.en_US
dc.date.accessioned2018-07-11T18:51:12Zen_US
dc.date.available2018-07-11T18:51:12Zen_US
dc.date.issued2018en_US
dc.description.abstractCollagen lysyl hydroxylases (LH1-3) are Fe2+- and 2-oxoglutarate (2-OG)-dependent oxygenases that maintain extracellular matrix homeostasis. High LH2 levels cause stable collagen cross-link accumulations that promote fibrosis and cancer progression. However, developing LH antagonists will require structural insights. Here, we report a 2 Å crystal structure and X-ray scattering on dimer assemblies for the LH domain of L230 in Acanthamoeba polyphaga mimivirus. Loop residues in the double-stranded β-helix core generate a tail-to-tail dimer. A stabilizing hydrophobic leucine locks into an aromatic tyrosine-pocket on the opposite subunit. An active site triad coordinates Fe2+. The two active sites flank a deep surface cleft that suggest dimerization creates a collagen-binding site. Loss of Fe2+-binding disrupts the dimer. Dimer disruption and charge reversal in the cleft increase Km and reduce LH activity. Ectopic L230 expression in tumors promotes collagen cross-linking and metastasis. These insights suggest inhibitor targets for fibrosis and cancer.en_US
dc.identifier.citationGuo, Hou-Fu, Tsai, Chi-Lin, Terajima, Masahiko, et al.. "Pro-metastatic collagen lysyl hydroxylase dimer assemblies stabilized by Fe2+-binding." <i>Nature Communications,</i> 9, (2018) Springer Nature: https://doi.org/10.1038/s41467-018-02859-z.en_US
dc.identifier.doihttps://doi.org/10.1038/s41467-018-02859-zen_US
dc.identifier.urihttps://hdl.handle.net/1911/102393en_US
dc.language.isoengen_US
dc.publisherSpringer Natureen_US
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titlePro-metastatic collagen lysyl hydroxylase dimer assemblies stabilized by Fe2+-bindingen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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