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Intra- and intersubunit ion-pair interactions determine the ability of apolipoprotein C-II mutants to form hybrid amyloid fibrils

journal contribution
posted on 2024-11-02, 04:50 authored by Nevena TodorovaNevena Todorova, Courtney Zlatic, Yu Mao, Irene YarovskyIrene Yarovsky, Geoffrey Howlett, Paul Gooley, Michael Griffin
The apolipoprotein family is structurally defined by amphipathic α-helical regions that interact with lipid surfaces. In the absence of lipid, human apolipoprotein (apo) C-II also forms well-defined amyloid fibrils with cross-β structure. Formation of this β-structure is accompanied by the burial of two charged residues, K30 and D69, that form an ion-pair within the amyloid fibril core. Molecular dynamics (MD) simulations indicate these buried residues form both intra- and intersubunit ion-pair interactions that stabilize the fibril. Mutations of the ion-pair (either K30D or D69K) reduce fibril stability and prevent fibril formation by K30D apoC-II under standard conditions. We investigated whether mixing K30D apoC-II with other mutants would overcome this loss of fibril forming ability. Co-incubation of equimolar mixtures of K30D apoC-II with wild-type, D69K, or double-mutant (K30D/D69K) apoC-II promoted the incorporation of K30D apoC-II into hybrid fibrils with increased stability. MD simulations showed an increase in the number of intersubunit ion-pair interactions accompanied the increased stability of the hybrid fibrils. These results demonstrate the important role of both intra- and intersubunit charge interactions in stabilizing apoC-II amyloid fibrils, a process that may be a key factor in determining the general ability of proteins to form amyloid fibrils.

Funding

The function and misfunction of serum apolipoproteins: lipid binding and protein misfolding

Australian Research Council

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History

Journal

Biochemistry

Volume

56

Issue

12

Start page

1757

End page

1767

Total pages

11

Publisher

American Chemical Society

Place published

United States

Language

English

Copyright

© 2017 American Chemical Society

Former Identifier

2006077591

Esploro creation date

2020-06-22

Fedora creation date

2017-09-13

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