Structural Insight into DNA-Dependent Activation of Human Metalloprotease Spartan

Faxiang Li, Joanna E. Raczynska, Zhe Chen, Hongtao Yu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The DNA-dependent metalloprotease Spartan (SPRTN) cleaves DNA-protein crosslinks (DPCs) and protects cells from DPC-induced genome instability. Germline mutations of SPRTN are linked to human Ruijs-Aalfs syndrome (RJALS) characterized by progeria and early-onset hepatocellular carcinoma. The mechanism of DNA-mediated activation of SPRTN is not understood. Here, we report the crystal structure of the human SPRTN SprT domain bound to single-stranded DNA (ssDNA). Our structure reveals a Zn 2+ -binding sub-domain (ZBD) in SprT that shields its active site located in the metalloprotease sub-domain (MPD). The narrow catalytic groove between MPD and ZBD only permits cleavage of flexible substrates. The ZBD contains an ssDNA-binding site, with a DNA-base-binding pocket formed by aromatic residues. Mutations of ssDNA-binding residues diminish the protease activity of SPRTN. We propose that the ZBD contributes to the ssDNA specificity of SPRTN, restricts the access of globular substrates, and positions DPCs, which may need to be partially unfolded, for optimal cleavage.

Original languageEnglish (US)
Pages (from-to)3336-3346.e4
JournalCell Reports
Volume26
Issue number12
DOIs
StatePublished - Mar 19 2019

Fingerprint

Metalloproteases
Single-Stranded DNA
Chemical activation
DNA
Progeria
Proteins
Germ-Line Mutation
Genomic Instability
Substrates
Hepatocellular Carcinoma
Catalytic Domain
Peptide Hydrolases
Genes
Crystal structure
Binding Sites
Mutation

Keywords

  • DNA repair
  • DNA-protein crosslinks
  • genome instability
  • metalloprotease
  • RJALS
  • Spartan
  • Zn binding

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Structural Insight into DNA-Dependent Activation of Human Metalloprotease Spartan. / Li, Faxiang; Raczynska, Joanna E.; Chen, Zhe; Yu, Hongtao.

In: Cell Reports, Vol. 26, No. 12, 19.03.2019, p. 3336-3346.e4.

Research output: Contribution to journalArticle

Li, Faxiang ; Raczynska, Joanna E. ; Chen, Zhe ; Yu, Hongtao. / Structural Insight into DNA-Dependent Activation of Human Metalloprotease Spartan. In: Cell Reports. 2019 ; Vol. 26, No. 12. pp. 3336-3346.e4.
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