Browsing by Author "Alvarado, Sarah K."

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    Pro-metastatic collagen lysyl hydroxylase dimer assemblies stabilized by Fe2+-binding
    (Springer Nature, 2018) Guo, Hou-Fu; Tsai, Chi-Lin; Terajima, Masahiko; Tan, Xiaochao; Banerjee, Priyam; Miller, Mitchell D.; Liu, Xin; Yu, Jiang; Byemerwa, Jovita; Alvarado, Sarah K.; Kaoud, Tamer S.; Dalby, Kevin N.; Bota-Rabassedas, Neus; Chen, Yulong; Yamauchi, Mitsuo; Tainer, John A.; Phillips, George N.Jr.; Kurie, Jonathan M.
    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.