@article{60aa4402547f4dcbbd2a16b2fb6f1647,
title = "Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy",
abstract = "High resolution structural information on amyloid fibrils is crucial for the understanding of their formation mechanisms and for the rational design of amyloid inhibitors in the context of protein misfolding diseases. The Src-homology 3 domain of phosphatidyl-inositol-3-kinase (PI3K-SH3) is a model amyloid system that plays a pivotal role in our basic understanding of protein misfolding and aggregation. Here, we present the atomic model of the PI3K-SH3 amyloid fibril with a resolution determined to 3.4 angstrom by cryo-electron microscopy (cryo-EM). The fibril is composed of two intertwined protofilaments that create an interface spanning 13 residues from each monomer. The model comprises residues 1-77 out of 86 amino acids in total, with the missing residues located in the highly flexible C-terminus. The fibril structure allows us to rationalise the effects of chemically conservative point mutations as well as of the previously reported sequence perturbations on PI3K-SH3 fibril formation and growth.",
keywords = "COMMON MECHANISM, DOMAIN, AGGREGATION, OLIGOMERS, KINETICS, FEATURES, IMPLIES, RESIDUE, MODEL, STATE",
author = "Christine Roeder and Nicola Vettore and Mangels, {Lena N.} and Lothar Gremer and Rayelli, {Raimond Bg} and Dieter Willbold and Wolfgang Hoyer and Buell, {Alexander K.} and Schr{\"o}der, {Gunnar F.}",
note = "Funding Information: We thank P.J. Peters and C. L{\'o}pez-Iglesias for their advice and helpful discussions, H. Duimel for help with sample preparation, and the M4I Division of Nanoscopy of Maastricht University for microscope access and support. We thank P. Neudecker for helpful comments on the paper. We gratefully acknowledge the computing time granted by the J{\"u}lich Aachen Research Alliance High-Peformance Computing (JARA-HPC) Vergabegremium and VSR commission on the supercomputer JURECA at For-schungszentrum J{\"u}lich. Computational support and infrastructure was provided by the Center for Information and Media Technology (ZIM) at the University of D{\"u}sseldorf (Germany). A.K.B. and N.V. thank the Deutsche Forschungsgemeinschaft (DFG) for funding. D.W. was supported by grants from the Portfolio Technology and Medicine, the Portfolio Drug Design, and the Helmholtz-Validierungsfonds of the Impuls und Vernetzungs-Fonds der Helmholtzgemeinschaft. This study was funded in part by the DFG SFB 974 and SFB 1208 (to D.W.). Support from a European Research Council (ERC) Consolidator Grant (grant agreement no. 726368) to W.H. is acknowledged. A.K.B. thanks the Novo Nordisk Foundation for support through a Novo Nordisk Foundation Professorship. Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = aug,
day = "21",
doi = "10.1038/s41467-019-11320-8",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}