Novel quaternary structures of the human prion protein globular domain

Autor(es):Mostrar menos -

Bortot, Leandro Oliveira ^[1] ; Rangel, Victor Lopes ^[1] ; Pavlovici, Francesca A. ^[2] ; El Omari, Kamel ^[3] ; Wagner, Armin ^[3] ; Brandao-Neto, Jose ^[3] ; Talon, Romain ^[3] ; von Delft, Frank ^{[4, 5, 3]} ; Reidenbach, Andrew G. ^[2] ; Vallabh, Sonia M. ^[2] ; Minikel, Eric Vallabh ^[2] ; Schreiber, Stuart ^{[6, 2]} ; Nonato, Maria Cristina ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Lab Prot Crystallog, Ribeirao Preto, SP - Brazil

^[2] Broad Inst MIT & Harvard, Chem Biol & Therapeut Sci Program, Cambridge, MA 02142 - USA

^[3] Diamond Light Source, Harwell Sci & Innovat Campus, Didcot, Oxon - England

^[4] Univ Oxford, Struct Genom Consortium, Old Rd Campus, Roosevelt Dr, Headington OX3 7DQ - England

^[5] Univ Johannesburg, Dept Biochem, ZA-2006 Auckland Pk - South Africa

^[6] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 - USA

• Tipo de documento: Artigo Científico
• Fonte: Biochimie; v. 191, p. 118-125, DEC 2021.
• Citações Web of Science: 0

Resumo

Prion disease is caused by the misfolding of the cellular prion protein, PrPC, into a self-templating conformer, PrPSc. Nuclear magnetic resonance (NMR) and X-ray crystallography revealed the 3D structure of the globular domain of PrPC and the possibility of its dimerization via an interchain disulfide bridge that forms due to domain swap or by non-covalent association of two monomers. On the contrary, PrPSc is composed by a complex and heterogeneous ensemble of poorly defined conformations and quaternary arrangements that are related to different patterns of neurotoxicity. Targeting PrPC with molecules that stabilize the native conformation of its globular domain emerged as a promising approach to develop anti-prion therapies. One of the advantages of this approach is employing structure-based drug discovery methods to PrPC. Thus, it is essential to expand our structural knowledge about PrPC as much as possible to aid such drug discovery efforts. In this work, we report a crystallographic structure of the globular domain of human PrPC that shows a novel dimeric form and a novel oligomeric arrangement. We use molecular dynamics simulations to explore its structural dynamics and stability and discuss potential implications of these new quaternary structures to the conversion process. (C) 2021 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. (AU)

• Processo FAPESP: 16/22929-0 - Biologia estrutural aplicada ao planejamento de ligantes para proteínas priônicas com fins terapêuticos.
• Beneficiário: Maria Cristina Nonato
• Modalidade de apoio: Bolsas no Exterior - Pesquisa
• Processo FAPESP: 17/26559-5 - Busca de fragmentos para a proteína priônica humana
• Beneficiário: Maria Cristina Nonato
• Modalidade de apoio: Auxílio à Pesquisa - Regular