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The crystal structure of human WD40 repeat-containing peptidylprolyl isomerase (PPWD1)

Tara L Davis1, John R Walker, Hui Ouyang

  • 1Structural Genomics Consortium, Banting Institute, University of Toronto, ON, Canada.

The FEBS Journal
|April 10, 2008
PubMed

Insights

The study reveals how PPWD1, a spliceosome cyclophilin, binds to itself like a substrate. This self-binding mechanism may explain its function within the spliceosome complex.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Cyclophilins are essential peptidylprolyl isomerases present in diverse organisms.
  • Human cyclophilins, like PPWD1, often possess multiple domains, with specific functions frequently undetermined.
  • PPWD1 is a spliceosome-associated cyclophilin containing WD40 repeats.

Purpose of the Study:

  • To elucidate the structure and potential function of the isomerase domain of PPWD1.
  • To investigate the interaction of PPWD1 with itself and its implications for spliceosome function.

Main Methods:

  • X-ray crystallography was used to determine the 1.65 Å structure of the PPWD1 isomerase domain.
  • Nuclear Magnetic Resonance (NMR) spectroscopy was employed to study the binding interactions in solution.

Main Results:

  • The crystal structure revealed that the N-terminus of one PPWD1 isomerase domain binds to the active site of a neighboring molecule, mimicking substrate binding.
  • NMR studies confirmed this self-binding interaction, demonstrating that the enzyme cannot process this pseudo-substrate.

Conclusions:

  • PPWD1 exhibits a unique pseudo-substrate mechanism where its N-terminus inhibits its own active site.
  • This auto-inhibitory mechanism likely plays a crucial role in regulating PPWD1's function within the human spliceosome.

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