Amyloidogenicity as a driving force for the formation of functional oligomers

WANG, WEIQIANG; BAKULINA, ANASTASIA; DUMAS, CHRISTIAN; ANIKEENKO, ALEXEY; GARRO, ADRIANA; VENTURA, SALVADOR; AZIZYAN, RAFAYEL A.; RADKOVA, ZINAIDA; CHARLIER, LANDRY; KAJAVA, ANDREY V.

JOURNAL OF STRUCTURAL BIOLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2020 vol. 212

1047-8477

Insoluble amyloid fibrils formed by self-assembly of amyloidogenic regions of proteins have a cross-β-structure. In this work, by using targeted molecular dynamics and rigid body simulation, we demonstrate that if a protein consists of an amyloidogenic region and a globular domain(s) and if the linker between them is short enough, such molecules cannot assemble into amyloid fibrils, instead, they form oligomers with a defined and limited number of β-strands in the cross-β core. We show that this blockage of the amyloid growth is due to the steric repulsion of the globular structures linked to amyloidogenic regions. Furthermore, we establish a relationship between the linker length and the number of monomers in such nanoparticles. We hypothesise that such oligomerisation can be a yet unrecognised way to form natural protein complexes involved in biological processes. Our results can also be used in protein engineering for designing soluble nanoparticles carrying different functional domains.