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

Article scientifique 2018 Anglais

Résumé

Abstract Collagen 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.

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Guo, H., Tsai, C., Terajima, M., Tan, X., Banerjee, P., Miller, M., Liu, X., Jiang, Y., Byemerwa, J., Alvarado, S., Kaoud, T., Dalby, K., Bota‐Rabassedas, N., Chen, Y., Yamauchi, M., Tainer, J., Kurie, J. (2018). Pro-metastatic collagen lysyl hydroxylase dimer assemblies stabilized by Fe2+-binding. https://doi.org/10.1038/s41467-018-02859-z

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Auteur(s)

Hou‐Fu Guo Chi-Lin Tsai Masahiko Terajima Xiaochao Tan Priyam Banerjee Mitchell D. Miller Xin Liu Yu Jiang Jovita Byemerwa Sarah Alvarado Tamer S. Kaoud Kevin N. Dalby Neus Bota‐Rabassedas Yulong Chen Mitsuo Yamauchi John A. Tainer Jonathan M. Kurie

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