Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy

Christine Röder, Nicola Vettore, Lena N. Mangels, Lothar Gremer, Raimond B G Ravelli, Dieter Willbold, Wolfgang Hoyer, Alexander K Buell, Gunnar F. Schröder*

*Corresponding author for this work

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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 Å 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.
Original languageEnglish
Article number3754
JournalNature Communications
Volume10
Issue number1
Number of pages9
ISSN2041-1723
DOIs
Publication statusPublished - 2019

Cite this

Röder, C., Vettore, N., Mangels, L. N., Gremer, L., Ravelli, R. B. G., Willbold, D., ... Schröder, G. F. (2019). Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy. Nature Communications, 10(1), [3754]. https://doi.org/10.1038/s41467-019-11320-8
Röder, Christine ; Vettore, Nicola ; Mangels, Lena N. ; Gremer, Lothar ; Ravelli, Raimond B G ; Willbold, Dieter ; Hoyer, Wolfgang ; Buell, Alexander K ; Schröder, Gunnar F. / Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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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 {\AA} 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.",
author = "Christine R{\"o}der and Nicola Vettore and Mangels, {Lena N.} and Lothar Gremer and Ravelli, {Raimond B G} and Dieter Willbold and Wolfgang Hoyer and Buell, {Alexander K} and Schr{\"o}der, {Gunnar F.}",
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Röder, C, Vettore, N, Mangels, LN, Gremer, L, Ravelli, RBG, Willbold, D, Hoyer, W, Buell, AK & Schröder, GF 2019, 'Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy', Nature Communications, vol. 10, no. 1, 3754. https://doi.org/10.1038/s41467-019-11320-8

Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy. / Röder, Christine; Vettore, Nicola; Mangels, Lena N.; Gremer, Lothar; Ravelli, Raimond B G; Willbold, Dieter; Hoyer, Wolfgang; Buell, Alexander K; Schröder, Gunnar F.

In: Nature Communications, Vol. 10, No. 1, 3754, 2019.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy

AU - Röder, Christine

AU - Vettore, Nicola

AU - Mangels, Lena N.

AU - Gremer, Lothar

AU - Ravelli, Raimond B G

AU - Willbold, Dieter

AU - Hoyer, Wolfgang

AU - Buell, Alexander K

AU - Schröder, Gunnar F.

PY - 2019

Y1 - 2019

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AB - 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 Å 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.

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Röder C, Vettore N, Mangels LN, Gremer L, Ravelli RBG, Willbold D et al. Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy. Nature Communications. 2019;10(1). 3754. https://doi.org/10.1038/s41467-019-11320-8