2. Academic Validation
  3. Molecular architecture of the multifunctional collagen lysyl hydroxylase and glycosyltransferase LH3

Molecular architecture of the multifunctional collagen lysyl hydroxylase and glycosyltransferase LH3

  • Nat Commun. 2018 Aug 8;9(1):3163. doi: 10.1038/s41467-018-05631-5.
Luigi Scietti 1,  Antonella Chiapparino 1,  Francesca De Giorgi 1,  Marco Fumagalli 2,  Lela Khoriauli 3,  Solomon Nergadze 3,  Shibom Basu 4,  Vincent Olieric 4,  Lucia Cucca 5,  Blerida Banushi 6 7,  Antonella Profumo 5,  Elena Giulotto 3,  Paul Gissen 6 8,  Federico Forneris 9
Affiliations

Affiliations

  • 1 The Armenise-Harvard Laboratory of Structural Biology, Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9/A, 27100, Pavia, Italy.
  • 2 Laboratory of Biochemistry, Department of Biology and Biotechnology, University of Pavia, Via Taramelli 3/B, 27100, Pavia, Italy.
  • 3 Laboratory of Molecular Biology, Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9/A, 27100, Pavia, Italy.
  • 4 Swiss Light Source, Paul Scherrer Institut, Villigen, 5232, Switzerland.
  • 5 Laboratory of Analytical Chemistry, Department of Chemistry, University of Pavia, Via Taramelli 12, 27100, Pavia, Italy.
  • 6 MRC Laboratory for Molecular Cell Biology, University College London, London, WC1E 6BT, UK.
  • 7 Translational Research Institute, The University of Queensland Diamantina Institute, Princess Alexandra Hospital, 37 Kent Street, Brisbane, Australia.
  • 8 UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
  • 9 The Armenise-Harvard Laboratory of Structural Biology, Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9/A, 27100, Pavia, Italy. [email protected].
PMID: 30089812 DOI: 10.1038/s41467-018-05631-5
Abstract

Lysyl hydroxylases catalyze hydroxylation of collagen lysines, and sustain essential roles in extracellular matrix (ECM) maturation and remodeling. Malfunctions in these enzymes cause severe connective tissue disorders. Human lysyl hydroxylase 3 (LH3/PLOD3) bears multiple enzymatic activities, as it catalyzes collagen lysine hydroxylation and also their subsequent glycosylation. Our understanding of LH3 functions is currently hampered by lack of molecular structure information. Here, we present high resolution crystal structures of full-length human LH3 in complex with cofactors and donor substrates. The elongated homodimeric LH3 architecture shows two distinct catalytic sites at the N- and C-terminal boundaries of each monomer, separated by an accessory domain. The glycosyltransferase domain displays distinguishing features compared to other known glycosyltransferases. Known disease-related mutations map in close proximity to the catalytic sites. Collectively, our results provide a structural framework characterizing the multiple functions of LH3, and the molecular mechanisms of collagen-related diseases involving human lysyl hydroxylases.

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