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

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 A₄₅₉xxxA_463/464xxA₄₆₇ 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.