Structural Biology of Molecular Machines Group, Protein Structure & Function Programme, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Institut de Biologie Intégrative de la Cellule (I2BC), CEA, CNRS, Université Paris Sud, Université Paris-Saclay, Gif-sur-Yvette, France; Institut Fancois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-Aux-Roses, France
Pratibha Kumari
Laboratory of Physical Chemistry, ETH Zurich, Zurich, Switzerland
Daniel Mona
Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Medicine Area, Neuroscience Discovery, Roche Innovation Center Basel, Basel, Switzerland
Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Medicine Area, Neuroscience Discovery, Roche Innovation Center Basel, Basel, Switzerland
Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson’s disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1–121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50–57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.
