TY - JOUR

T1 - Amyloidogenicity as a driving force for the formation of functional oligomers

AU - Azizyan, Rafayel A.

AU - Wang, Weiqiang

AU - Anikeenko, Alexey

AU - Radkova, Zinaida

AU - Bakulina, Anastasia

AU - Garro, Adriana

AU - Charlier, Landry

AU - Dumas, Christian

AU - Ventura, Salvador

AU - Kajava, Andrey V.

N1 - Publisher Copyright: © 2020 Elsevier Inc. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

AB - 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.

KW - Amyloids

KW - Functional nanoparticles

KW - Rigid body simulation

KW - Targeted molecular dynamics

KW - PHASE-SEPARATION

KW - PRION DOMAIN

KW - AMYLOID FIBRILS

KW - MODELS

KW - SUP35P

KW - PARALLEL BETA-SHEET

KW - ALPHA-SYNUCLEIN

KW - AGGREGATION

UR - http://www.scopus.com/inward/record.url?scp=85089518419&partnerID=8YFLogxK

U2 - 10.1016/j.jsb.2020.107604

DO - 10.1016/j.jsb.2020.107604

M3 - Article

C2 - 32805411

AN - SCOPUS:85089518419

VL - 212

JO - Journal of Structural Biology

JF - Journal of Structural Biology

SN - 1047-8477

IS - 1

M1 - 107604

ER -