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

Hou-Fu Guo, Chi-Lin Tsai, Masahiko Terajima, Xiaochao Tan, Priyam Banerjee, Mitchell D. Miller, Xin Liu, Jiang Yu, Jovita Byemerwa, Sarah Alvarado, Tamer S. Kaoud, Kevin N. Dalby, Neus Bota-Rabassedas, Yulong Chen, Mitsuo Yamauchi, John A. Tainer (), George N. Phillips () and Jonathan M. Kurie ()
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Hou-Fu Guo: The University of Texas MD Anderson Cancer Center
Chi-Lin Tsai: The University of Texas MD Anderson Cancer Center
Masahiko Terajima: University of North Carolina at Chapel Hill
Xiaochao Tan: The University of Texas MD Anderson Cancer Center
Priyam Banerjee: The University of Texas MD Anderson Cancer Center
Mitchell D. Miller: Rice University
Xin Liu: The University of Texas MD Anderson Cancer Center
Jiang Yu: The University of Texas MD Anderson Cancer Center
Jovita Byemerwa: The University of Texas MD Anderson Cancer Center
Sarah Alvarado: Rice University
Tamer S. Kaoud: The University of Texas at Austin
Kevin N. Dalby: The University of Texas at Austin
Neus Bota-Rabassedas: The University of Texas MD Anderson Cancer Center
Yulong Chen: The University of Texas MD Anderson Cancer Center
Mitsuo Yamauchi: University of North Carolina at Chapel Hill
John A. Tainer: The University of Texas MD Anderson Cancer Center
George N. Phillips: Rice University
Jonathan M. Kurie: The University of Texas MD Anderson Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-02859-z

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