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

Christine Roeder, Nicola Vettore, Lena N. Mangels, Lothar Gremer, Raimond Bg Rayelli, Dieter Willbold, Wolfgang Hoyer, Alexander K. Buell*, Gunnar F. Schröder*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Web of Science)

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.

Original languageEnglish
Article number3754
Number of pages9
JournalNature Communications
Volume10
DOIs
Publication statusPublished - 21 Aug 2019

Keywords

  • COMMON MECHANISM
  • DOMAIN
  • AGGREGATION
  • OLIGOMERS
  • KINETICS
  • FEATURES
  • IMPLIES
  • RESIDUE
  • MODEL
  • STATE

Cite this