Molecular structure and enzymatic mechanism of the human collagen hydroxylysine galactosyltransferase GLT25D1/COLGALT1

Matteo De Marco, Sristi Raj Rai, Luigi Scietti, Daiana Mattoteia, Stefano Liberi, Elisabetta Moroni, Alberta Pinnola, Alice Vetrano, Claudio Iacobucci, Carlo Santambrogio, Giorgio Colombo and Federico Forneris ()
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Matteo De Marco: University of Pavia
Sristi Raj Rai: University of Pavia
Luigi Scietti: University of Pavia
Daiana Mattoteia: University of Pavia
Stefano Liberi: University of Pavia
Elisabetta Moroni: SCITEC-CNR
Alberta Pinnola: University of Pavia
Alice Vetrano: University of L’Aquila
Claudio Iacobucci: University of L’Aquila
Carlo Santambrogio: University of Milano-Bicocca
Giorgio Colombo: University of Pavia
Federico Forneris: University of Pavia

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract During collagen biosynthesis, lysine residues undergo extensive post-translational modifications through the alternate action of two distinct metal ion-dependent enzyme families (i.e., LH/PLODs and GLT25D/COLGALT), ultimately producing the highly conserved α-(1,2)-glucosyl-β-(1,O)-galactosyl-5-hydroxylysine pattern. Malfunctions in these enzymes are linked to developmental pathologies and extracellular matrix alterations associated to enhanced aggressiveness of solid tumors. Here, we characterized human GLT25D1/COLGALT1, revealing an elongated head-to-head homodimeric assembly. Each monomer encompasses two domains (named GT1 and GT2), both unexpectedly capable of binding metal ion cofactors and UDP-α-galactose donor substrates, resulting in four candidate catalytic sites per dimer. We identify the catalytic site in GT2, featuring an unusual Glu-Asp-Asp motif critical for Mn2+ binding, ruling out direct catalytic roles for the GT1 domain, but showing that in this domain the unexpectedly bound Ca2+ and UDP-α-galactose cofactors are critical for folding stability. Dimerization, albeit not essential for GLT25D1/COLGALT1 activity, provides a critical molecular contact site for multi-enzyme assembly interactions with partner multifunctional LH/PLOD lysyl hydroxylase-glycosyltransferase enzymes.

Date: 2025
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DOI: 10.1038/s41467-025-59017-5

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