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<p>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 Mn<sup>2+</sup> binding, ruling out direct catalytic roles for the GT1 domain, but showing that in this domain&#xa0;the unexpectedly bound Ca<sup>2+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月16日

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  • Matteo De Marco,
  • Sristi Raj Rai,
  • Luigi Scietti,
  • Daiana Mattoteia,
  • Stefano Liberi,
  • Elisabetta Moroni,
  • Alberta Pinnola,
  • Alice Vetrano,
  • Claudio Iacobucci,
  • Carlo Santambrogio,
  • Giorgio Colombo,
  • Federico Forneris

摘要

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.