Guo, Hou-FuTsai, Chi-LinTerajima, MasahikoTan, XiaochaoBanerjee, PriyamMiller, Mitchell D.Liu, XinYu, JiangByemerwa, JovitaAlvarado, Sarah K.Kaoud, Tamer S.Dalby, Kevin N.Bota-Rabassedas, NeusChen, YulongYamauchi, MitsuoTainer, John A.Phillips, George N.Jr.Kurie, Jonathan M.2018-07-112018-07-112018Guo, 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.https://hdl.handle.net/1911/102393Collagen 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.engThis 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.Journal articlehttps://doi.org/10.1038/s41467-018-02859-z