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<p>Collagen, the major structural protein in the animal extracellular matrix, forms a triple helix that resists proteolysis and requires specialised enzymes for degradation. Flesh-eating bacteria secrete collagenases that unwind the collagen triple helix and processively trim Gly–X–Y triplet repeats, yet the molecular basis of this process has remained obscure. Here, cryo-electron microscopy reveals how&#xa0;<i>Hathewaya</i> <i>histolytica</i> collagenase ColH engages its substrate and exploits the helix’s architecture for catalysis. ColH encircles a single collagen triple helix in a closed-ring conformation and, through dynamic domain motions, dehydrates and destabilises it. The enzyme undergoes substrate-assisted twisting to adopt a rigid ratcheted conformation, in which one chain is bent into a tripeptide-long ‘bight’ and threaded into the active site for cleavage, while two uncut strands are partitioned to non-catalytic sites. Release of the bight appears to reset the enzyme, with the uncut strands serving as guiding tracks. Repeated cycling between dynamic and rigid states likely enables triplet-by-triplet translocation, allowing ColH to harness collagen’s geometry for processive degradation. These findings reveal a bacterial strategy for collagen unwinding and cleavage distinct from that of mammalian collagenases, highlighting divergent evolutionary solutions for degrading one of nature’s most intractable substrates.</p>

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Bacterial collagenase harnesses collagen geometry for processive cleavage

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月2日

查看全文
  • Hiroya Oki,
  • Katsuki Takebe,
  • Adjoa Bonsu,
  • Kazunori Fujii,
  • Ryo Masuda,
  • Nicholas Henderson,
  • Takehiko Mima,
  • Takaki Koide,
  • Mahmoud Moradi,
  • Osamu Matsushita,
  • Joshua Sakon,
  • Kazuki Kawahara

摘要

Collagen, the major structural protein in the animal extracellular matrix, forms a triple helix that resists proteolysis and requires specialised enzymes for degradation. Flesh-eating bacteria secrete collagenases that unwind the collagen triple helix and processively trim Gly–X–Y triplet repeats, yet the molecular basis of this process has remained obscure. Here, cryo-electron microscopy reveals how Hathewaya histolytica collagenase ColH engages its substrate and exploits the helix’s architecture for catalysis. ColH encircles a single collagen triple helix in a closed-ring conformation and, through dynamic domain motions, dehydrates and destabilises it. The enzyme undergoes substrate-assisted twisting to adopt a rigid ratcheted conformation, in which one chain is bent into a tripeptide-long ‘bight’ and threaded into the active site for cleavage, while two uncut strands are partitioned to non-catalytic sites. Release of the bight appears to reset the enzyme, with the uncut strands serving as guiding tracks. Repeated cycling between dynamic and rigid states likely enables triplet-by-triplet translocation, allowing ColH to harness collagen’s geometry for processive degradation. These findings reveal a bacterial strategy for collagen unwinding and cleavage distinct from that of mammalian collagenases, highlighting divergent evolutionary solutions for degrading one of nature’s most intractable substrates.