6AX6

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

(2018) Nat Commun 9: 512-512

• PubMed: 29410444 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1038/s41467-018-02859-z
• Primary Citation of Related Structures:  
  6AX6, 6AX7


• PubMed Abstract: 
  

  Collagen lysyl hydroxylases (LH1-3) are Fe ²⁺ - 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 Fe ²⁺ . The two active sites flank a deep surface cleft that suggest dimerization creates a collagen-binding site. Loss of Fe ²⁺ -binding disrupts the dimer. Dimer disruption and charge reversal in the cleft increase K _m 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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Organizational Affiliation: 

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.