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Structural basis for Ca(2+)-induced activation of human PAD4
Kyouhei Arita1, Hiroshi Hashimoto, Toshiyuki Shimizu
1Graduate School of Integrated Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
Nature Structural & Molecular Biology
|July 13, 2004
Summary
Peptidylarginine deiminase 4 (PAD4) is an enzyme linked to rheumatoid arthritis. Structural studies reveal how calcium ions activate PAD4, offering insights for drug development.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Peptidylarginine deiminase 4 (PAD4) is a calcium-dependent enzyme implicated in rheumatoid arthritis pathogenesis.
- PAD4 catalyzes the citrullination of protein arginine residues, a post-translational modification relevant to autoimmune diseases.
Purpose of the Study:
- To elucidate the structural basis of PAD4 activation by calcium ions.
- To provide insights into the mechanism of enzyme activation for potential therapeutic targeting.
Main Methods:
- X-ray crystallography was employed to determine the structures of Ca(2+)-free and Ca(2+)-bound PAD4.
- Structural analysis focused on identifying calcium-binding sites and conformational changes upon ion binding.
Main Results:
- The crystal structure of Ca(2+)-free PAD4 revealed an elongated fold with distinct N-terminal and C-terminal domains.
- Five non-EF-hand calcium-binding sites were identified in the Ca(2+)-bound inactive mutant.
- Calcium binding induces conformational changes that form the active site cleft, revealing a novel activation mechanism.
Conclusions:
- Calcium ions activate PAD4 through a novel mechanism involving conformational changes that create the active site.
- Understanding this mechanism is crucial for developing PAD-inhibiting drugs for rheumatoid arthritis treatment.