title: Domains of STIP1 responsible for regulating PrPC-dependent amyloid-β oligomer toxicity.
abstract: Soluble oligomers of amyloid-beta peptide (AβO) transmit neurotoxic signals through the cellular prion protein (PrP(C)) in Alzheimer's disease (AD). Secreted stress-inducible phosphoprotein 1 (STIP1), an Hsp70 and Hsp90 cochaperone, inhibits AβO binding to PrP(C) and protects neurons from AβO-induced cell death. Here, we investigated the molecular interactions between AβO and STIP1 binding to PrP(C) and their effect on neuronal cell death. We showed that residues located in a short region of PrP (90-110) mediate AβO binding and we narrowed the major interaction in this site to amino acids 91-100. In contrast, multiple binding sites on STIP1 (DP1, TPR1 and TPR2A) contribute to PrP binding. DP1 bound the N-terminal of PrP (residues 23-95), whereas TPR1 and TPR2A showed binding to the C-terminal of PrP (residues 90-231). Importantly, only TPR1 and TPR2A directly inhibit both AβO binding to PrP and cell death. Furthermore, our structural studies reveal that TPR1 and TPR2A bind to PrP through distinct regions. The TPR2A interface was shown to be much more extensive and to partially overlap with the Hsp90 binding site. Our data show the possibility of a PrP, STIP1 and Hsp90 ternary complex, which may influence AβO-mediated cell death.
authors.affiliation: Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Maciejewski
authors.affiliation: Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8 Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8 Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8.
authors.forename: Valeriy G
authors.initials: VG
authors.lastname: Ostapchenko
authors.affiliation: Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8 Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8 Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8.
authors.forename: Flavio H
authors.initials: FH
authors.lastname: Beraldo
authors.affiliation: Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8 Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8 Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8.
authors.forename: Vania F
authors.initials: VF
authors.lastname: Prado
authors.affiliation: Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8 Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8 Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8 jchoy4@uwo.ca mprado@robarts.ca.
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
authors.affiliation: Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1 jchoy4@uwo.ca mprado@robarts.ca.
authors.forename: Wing-Yiu
authors.initials: WY
authors.lastname: Choy
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D006360:Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009474:Neurons / Q000378:metabolism; D018621:PrPC Proteins / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D006360:Heat-Shock Proteins; D018621:PrPC Proteins; C489791:Stip1 protein, mouse
keywords: Alzheimer's disease; cochaperone; neuronal cell death; neuroprotective; neurotoxicity