Structure of human lanthionine synthetase C-like protein 1 and its interaction with Eps8 and glutathione

Genes Dev. 2009 Jun 15;23(12):1387-92. doi: 10.1101/gad.1789209.

Abstract

Eukaryotic lanthionine synthetase C-like protein 1 (LanCL1) is homologous to prokaryotic lanthionine cyclases, yet its biochemical functions remain elusive. We report the crystal structures of human LanCL1, both free of and complexed with glutathione, revealing glutathione binding to a zinc ion at the putative active site formed by conserved GxxG motifs. We also demonstrate by in vitro affinity analysis that LanCL1 binds specifically to the SH3 domain of a signaling protein, Eps8. Importantly, expression of LanCL1 mutants defective in Eps8 interaction inhibits nerve growth factor (NGF)-induced neurite outgrowth, providing evidence for the biological significance of this novel interaction in cellular signaling and differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Escherichia coli / genetics
  • Gene Expression Regulation
  • Glutathione / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Models, Molecular
  • Mutation
  • Nerve Growth Factor / pharmacology
  • Neurites / physiology
  • Neurons / cytology
  • Neurons / drug effects
  • PC12 Cells
  • Protein Binding
  • Protein Structure, Tertiary
  • Rats
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Zinc / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • EPS8 protein, human
  • Intracellular Signaling Peptides and Proteins
  • LANCL1 protein, human
  • Receptors, G-Protein-Coupled
  • Recombinant Proteins
  • Nerve Growth Factor
  • Glutathione
  • Zinc