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

• Published in: Biochimica et biophysica acta. Biomembranes 2018-05, Vol.1860 (5), p.1105-1113
• Main Authors: Bittner, Heiko J., Guixà-González, Ramon, Hildebrand, Peter W.
• Format: Article
• Language: English
• Subjects: Alzheimer's Disease; Amyloid Precursor Protein Secretases - chemistry; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; BACE1; Beta-secretase; Channels and transporters; Copper; Copper - metabolism; Cysteine; Helix packing; Helix-Loop-Helix Motifs - genetics; Humans; Ion Transport - genetics; Ions - metabolism; MD simulations; Metal ion; Methionine; Models, Molecular; Molecular dynamics; Molecular Dynamics Simulation; Protein Binding - genetics; Protein Interaction Domains and Motifs - genetics; Protein Multimerization - genetics; Sulfur; Transmembrane domain; Transmembrane helix; Trimer
• ISSN: 0005-2736; 1879-2642
• DOI: 10.1016/j.bbamem.2018.01.019

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. [Display omitted] •BACE1 transmembrane helices self-assemble to predominantly right-handed trimers•A sulfur rich motif defines a constricted pore along the BACE1 trimer axis•Sliding and tilting of helices coordinate shifting of copper along the pore