Metal Ion Binding to Human Glutaminyl Cyclase: A Structural Perspective
Giusy Tassone1, Cecilia Pozzi1,2, Stefano Mangani1
1Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, I-53100 Siena, Italy.
International Journal of Molecular Sciences
|August 10, 2024
Summary
Glutaminyl-peptide cyclotransferases (QCs) stabilize proteins by forming pyroglutamate (pE). This study reveals the structure of human QC (hQC) with zinc and cobalt, offering insights into its catalytic mechanism and potential drug development for neurodegenerative diseases.
Area of Science:
- Biochemistry
- Enzymology
- Structural Biology
Background:
- Glutaminyl-peptide cyclotransferases (QCs) catalyze N-terminal pyroglutamate (pE) formation, enhancing peptide and protein stability.
- pE-modified peptides are implicated in neurodegenerative diseases like Alzheimer's and Huntington's, making human QC (hQC) a drug development target.
- hQC is a Zn-dependent enzyme, with some activity restored by Co(II), suggesting a potential catalytic role for cobalt.
Purpose of the Study:
- To investigate the structure of demetallated hQC and its reconstituted forms with Zn(II) and Co(II).
- To analyze the behavior of these hQC forms in the presence of known inhibitors.
- To provide structural insights into the mononuclear metal binding site of hQC.
Main Methods:
- X-ray crystallography to determine the structure of demetallated and metal-reconstituted hQC.
- Enzyme activity assays in the presence of inhibitors.
- Comparative structural analysis with related metalloenzymes.
Main Results:
- Structural determination of demetallated hQC and its complexes with Zn(II) and Co(II).
- Characterization of enzyme inhibition profiles.
- Structural basis for the mononuclear metal binding site in hQC, distinct from dinuclear metalloenzymes.
Conclusions:
- The structural data elucidate the role of metal ions in hQC activity and inhibition.
- Findings provide a foundation for structure-based drug design targeting hQC for neurodegenerative diseases.
- The study clarifies the unique mononuclear metal coordination in hQC compared to related enzymes.
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