Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme

• Main Authors: Phillips, Margaret, Kannaian, Bhuvaneswari, Ng, Justin Tze-Yang, Kather, Ralf, Mu, Yuguang, Harmer, Jeffrey R., Pervushin, Konstantin
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2022
• Subjects: Science::Biological sciences; Electron-Paramagnetic-Resonance; Site-Directed Mutagenesis
• Online Access: https://hdl.handle.net/10356/161448
• Institution: Nanyang Technological University

The extracellular transporter, lipocalin-type prostaglandin D synthase (L-PGDS) binds to heme and heme metabolites with high affinity. It has been reported that L-PGDS protects neuronal cells against apoptosis induced by exposure to hydrogen peroxide. Our study demonstrates that when human WT L-PGDS is in complex with heme, it exhibits a strong peroxidase activity thus behaving as a pseudo-peroxidase. Electron paramagnetic resonance studies confirm that heme in the L-PGDS-heme complex is hexacoordinated with high-spin Fe(III). NMR titration of heme in L-PGDS points to hydrophobic interaction between heme and several residues within the β-barrel cavity of L-PGDS. In addition to the transporter function, L-PGDS is a key amyloid β chaperone in human cerebrospinal fluid. The presence of high levels of bilirubin and its derivatives, implicated in Alzheimer's disease, by binding to L-PGDS may reduce its chaperone activity. Nevertheless, our ThT binding assay establishes that heme and heme metabolites do not significantly alter the neuroprotective chaperone function of L-PGDS. Guided by NMR data we reconstructed the heme L-PGDS complex using extensive molecular dynamics simulations providing a platform for mechanistic interpretation of the catalytic and transporting functions and their modulation by secondary ligands like Aβ peptides and heme metabolites.