Title
HIV Tat protein and amyloid-β peptide form multifibrillar structures that cause neurotoxicity
Author
Alina Hategan, Mario A Bianchet, Joseph Steiner, Elena Karnaukhova, Eliezer Masliah, Adam Fields, Myoung-Hwa Lee, Alex M Dickens, Norman Haughey, Emilios K Dimitriadis, Avindra Nath
Year
2017
Journal
Nature Structural & Molecular Biology
Abstract
Deposition of amyloid- plaques is increased in the brains of HIV-infected individuals, and the HIV transactivator of transcription (Tat) protein affects amyloidogenesis through several indirect mechanisms. Here, we investigated direct interactions between Tat and amyloid- peptide. Our in vitro studies showed that in the presence of Tat, uniform amyloid fibrils become double twisted fibrils and further form populations of thick unstructured filaments and aggregates. Specifically, Tat binding to the exterior surfaces of the A fibrils increases -sheet formation and lateral aggregation into thick multifibrillar structures, thus producing fibers with increased rigidity and mechanical resistance. Furthermore, Tat and A aggregates in complex synergistically induced neurotoxicity both in vitro and in animal models. Increased rigidity and mechanical resistance of the amyloid-–Tat complexes coupled with stronger adhesion due to the presence of Tat in the fibrils may account for increased damage, potentially through pore formation in membranes.
Instrument
J-815
Keywords
Circular dichroism, Secondary structure, Aggregation, Biochemistry