8.A.32 The β-Amyloid Cleaving Enzyme 1 (BACE1) Family

BACE1 (β-secretase1 precursor; β-APP cleaving enzyme; β-amyloid precursor protein) activity is significantly increased in the brains of Alzheimer's disease patients, potentially contributing to neurodegeneration. The voltage-gated sodium channel (Na(v)1) β2-subunit (β2), a type I membrane protein that covalently binds to Na(v)1 α-subunits, is a substrate for BACE1 and γ-secretase. BACE1-γ-secretase cleavages release the intracellular domain of β2, which increases mRNA and protein levels of the pore-forming Na(v)1.1 α-subunit in neuroblastoma cells. Similarly, endogenous β2 processing and Na(v)1.1 protein levels are elevated in brains of BACE1-transgenic mice and Alzheimer's disease patients with high BACE1 levels. However, Na(v)1.1 is retained inside the cell, and cell surface expression of the Na(v)1 α-subunits and sodium current densities are markedly reduced in both neuroblastoma cells and adult hippocampal neurons from BACE1-transgenic mice. BACE1, by cleaving beta2, thus regulates Na(v)1 α-subunit levels and controls cell-surface sodium current densities. BACE1 inhibitors may normalize membrane excitability in Alzheimer's disease patients with elevated BACE1 activity (Kim et al., 2007).

Secretases generate amyloid β-peptides which cause Alzheimer's disease (Steiner et al., 2006). The γ-secretase complex, consisting of four proteins, catalyzes intramembranous proteolysis. The complex is a spherical transmembrane particle with an interior chamber that accommodates its catalytic residues and the substrate protein. Two potential exit sites have been visualized by electron microscopy (Steiner et al., 2006). Transmembrane domain 9 of presenilin determines the dynamic conformation of the catalytic site of γ-secretase (Tolia et al., 2008).

BACE1 regulates neuronal excitability through an unorthodox, nonenzymatic interaction with members of the KCNQ (Kv7) family that give rise to M-currents, noninactivating potassium currents with slow kinetics (Hessler et al. 2015). In hippocampal neurons from BACE1(-/-) mice, loss of M-current enhanced neuronal excitability. The diminished M-current was comparable to the previously reported epileptic phenotype of BACE1-deficient mice.  BACE1 amplified reconstituted M-currents, altered their voltage dependence, accelerated activation, and slowed deactivation. Biochemical evidence suggested that BACE1 physically associates with channel proteins in a beta-subunit-like fashion, establishing that BACE1 as a physiological constituent of M-currents (Hessler et al. 2015).

BACE1 has a unique sulfur rich motif (M462xxxC466xxxM470xxxC474xxxC478) in its TMS which is characteristic for proteins involved in copper ion storage and transport. This motif has been shown to promote BACE1 trimerization and binding of copper ions in vitro. Membrane-embedded BACE1 adopts a flexible trimeric structure that binds and conducts copper ions (Bittner et al. 2018). The spontaneous assembly of BACE1 trimers results in a right-handed helix packing arrangement. 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. Structural arrangement of BACE1-TM trimers and a mechanism for copper ion conduction have been proposed (Bittner et al. 2018). Thus, BACE1 may be a copper transporter in addition to its other functions.