TY - JOUR

T1 - Establishment of Constraints on Amyloid Formation Imposed by Steric Exclusion of Globular Domains

AU - Azizyan, Rafayel A.

AU - Garro, Adriana

AU - Radkova, Zinaida

AU - Anikeenko, Alexey

AU - Bakulina, Anastasia

AU - Dumas, Christian

AU - Kajava, Andrey V.

N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.

PY - 2018/10/12

Y1 - 2018/10/12

N2 - In many disease-related and functional amyloids, the amyloid-forming regions of proteins are flanked by globular domains. When located in close vicinity of the amyloid regions along the chain, the globular domains can prevent the formation of amyloids because of the steric repulsion. Experimental tests of this effect are few in number and non-systematic, and their interpretation is hampered by polymorphism of amyloid structures. In this situation, modeling approaches that use such a clear-cut criterion as the steric tension can give us highly trustworthy results. In this work, we evaluated this steric effect by using molecular modeling and dynamics. As an example, we tested hybrid proteins containing an amyloid-forming fragment of Aβ peptide (17–42) linked to one or two globular domains of GFP. Searching for the shortest possible linker, we constructed models with pseudo-helical arrangements of the densely packed GFPs around the Aβ amyloid core. The molecular modeling showed that linkers of 7 and more residues allow fibrillogenesis of the Aβ-peptide flanked by GFP on one side and 18 and more residues when Aβ-peptide is flanked by GFPs on both sides. Furthermore, we were able to establish a more general relationship between the size of the globular domains and the length of the linkers by using analytical expressions and rigid body simulations. Our results will find use in planning and interpretation of experiments, improvement of the prediction of amyloidogenic regions in proteins, and design of new functional amyloids carrying globular domains.

AB - In many disease-related and functional amyloids, the amyloid-forming regions of proteins are flanked by globular domains. When located in close vicinity of the amyloid regions along the chain, the globular domains can prevent the formation of amyloids because of the steric repulsion. Experimental tests of this effect are few in number and non-systematic, and their interpretation is hampered by polymorphism of amyloid structures. In this situation, modeling approaches that use such a clear-cut criterion as the steric tension can give us highly trustworthy results. In this work, we evaluated this steric effect by using molecular modeling and dynamics. As an example, we tested hybrid proteins containing an amyloid-forming fragment of Aβ peptide (17–42) linked to one or two globular domains of GFP. Searching for the shortest possible linker, we constructed models with pseudo-helical arrangements of the densely packed GFPs around the Aβ amyloid core. The molecular modeling showed that linkers of 7 and more residues allow fibrillogenesis of the Aβ-peptide flanked by GFP on one side and 18 and more residues when Aβ-peptide is flanked by GFPs on both sides. Furthermore, we were able to establish a more general relationship between the size of the globular domains and the length of the linkers by using analytical expressions and rigid body simulations. Our results will find use in planning and interpretation of experiments, improvement of the prediction of amyloidogenic regions in proteins, and design of new functional amyloids carrying globular domains.

KW - aggregation

KW - amyloids

KW - fibrillogenesis

KW - protein structure

KW - rigid body simulation

KW - PROTEIN

KW - MOLECULAR-STRUCTURE

KW - POLYMORPHISM

KW - MODEL

KW - PEPTIDE

KW - ORGANIZATION

KW - FIBRILS

KW - FILAMENTS

KW - DYNAMICS

KW - AGGREGATION

KW - Peptide Fragments/chemistry

KW - Amyloid beta-Peptides/chemistry

KW - Protein Domains

KW - Protein Interaction Domains and Motifs

KW - Recombinant Fusion Proteins/chemistry

KW - Amino Acid Sequence

KW - Amyloid/chemistry

KW - Models, Molecular

KW - Protein Binding

KW - Protein Conformation

UR - http://www.scopus.com/inward/record.url?scp=85048705937&partnerID=8YFLogxK

U2 - 10.1016/j.jmb.2018.05.038

DO - 10.1016/j.jmb.2018.05.038

M3 - Article

C2 - 29860028

AN - SCOPUS:85048705937

VL - 430

SP - 3835

EP - 3846

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 20

ER -