Intra- and Intersubunit Ion-Pair Interactions Determine the Ability of Apolipoprotein C-II Mutants To Form Hybrid Amyloid Fibrils.

Autor:	Todorova N; School of Engineering, RMIT University , GPO Box 2476V, Melbourne, Victoria 3001, Australia., Zlatic CO; Department of Biochemistry and Molecular Biology, University of Melbourne , Parkville, Victoria 3010, Australia.; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville, Victoria 3010, Australia., Mao Y; Department of Biochemistry and Molecular Biology, University of Melbourne , Parkville, Victoria 3010, Australia.; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville, Victoria 3010, Australia., Yarovsky I; School of Engineering, RMIT University , GPO Box 2476V, Melbourne, Victoria 3001, Australia., Howlett GJ; Department of Biochemistry and Molecular Biology, University of Melbourne , Parkville, Victoria 3010, Australia.; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville, Victoria 3010, Australia., Gooley PR; Department of Biochemistry and Molecular Biology, University of Melbourne , Parkville, Victoria 3010, Australia.; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville, Victoria 3010, Australia., Griffin MD; Department of Biochemistry and Molecular Biology, University of Melbourne , Parkville, Victoria 3010, Australia.; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville, Victoria 3010, Australia.
Jazyk:	angličtina
Zdroj:	Biochemistry [Biochemistry] 2017 Mar 28; Vol. 56 (12), pp. 1757-1767. Date of Electronic Publication: 2017 Mar 15.
DOI:	10.1021/acs.biochem.6b01146
Abstrakt:	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.
Databáze:	MEDLINE
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