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Biochim Biophys Acta Biomembr. 2018 May;1860(5):1105-1113. doi: 10.1016/j.bbamem.2018.01.019. Epub 2018 Jan 31.

Structural basis for the interaction of the beta-secretase with copper.

Author information

1
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Medical Physics and Biophysics {Institut für Medizinische Physik und Biophysik}, AG ProteInFormatics, Charitéplatz 1, 10117 Berlin, Germany; Faculty of Medicine, Leipzig University, Institute for Medical Physics and Biophysics {Institut für Medizinische Physik und Biophysik}, Härtelstr. 16-18, 04107 Leipzig, Germany. Electronic address: Heiko.Bittner@charite.de.
2
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Medical Physics and Biophysics {Institut für Medizinische Physik und Biophysik}, AG ProteInFormatics, Charitéplatz 1, 10117 Berlin, Germany. Electronic address: Ramon.Guixa-Gonzalez@charite.de.
3
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Medical Physics and Biophysics {Institut für Medizinische Physik und Biophysik}, AG ProteInFormatics, Charitéplatz 1, 10117 Berlin, Germany; Faculty of Medicine, Leipzig University, Institute for Medical Physics and Biophysics {Institut für Medizinische Physik und Biophysik}, Härtelstr. 16-18, 04107 Leipzig, Germany. Electronic address: Peter.Hildebrand@charite.de.

Abstract

The β-secretase (BACE1) features a unique sulfur rich motif (M462xxxC466xxxM470xxxC474xxxC478) in its transmembrane helix (BACE1-TM) which is characteristic for proteins involved in copper ion storage and transport. While this motif has been shown to promote BACE1-TM trimerization and binding of copper ions in vitro, the structural basis for the interaction of copper ions with the BACE1-TM is still not well understood. Using molecular dynamics (MD) simulations, we show that membrane embedded BACE1-TMs adopt a flexible trimeric structure that binds and conducts copper ions through variable coordination. In coarse-grained (CG) MD simulations, the spontaneous assembly of BACE1-TMs trimers results in a right-handed helix packing arrangement. In subsequent atomistic MD simulations the sulfur rich motif defines characteristic copper ion coordination sites along a constricted partially solvated axial pore. Sliding and tilting of BACE1-TMs along smooth A459xxxA463/464xxA467 surfaces, facilitated by a central P472 induced kink, enables copper ions to alternate between different coordination sites, including the prominent C466 and M470. We shed light into the structural arrangement of BACE1-TM trimers and propose a mechanism for copper ion conduction that might also apply to other proteins involved in metal ion transport.

KEYWORDS:

Alzheimer's Disease; BACE1; Beta-secretase; Channels and transporters; Copper; Cysteine; Helix packing; MD simulations; Metal ion; Methionine; Molecular dynamics; Sulfur; Transmembrane domain; Transmembrane helix; Trimer

PMID:
29391167
DOI:
10.1016/j.bbamem.2018.01.019
[Indexed for MEDLINE]
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