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.



This family belongs to the .

 

References:

Bittner, H.J., R. Guixà-González, and P.W. Hildebrand. (2018). Structural basis for the interaction of the β-secretase with copper. Biochim. Biophys. Acta. 1860: 1105-1113. [Epub: Ahead of Print]

Hassan, M.I., A. Toor, and F. Ahmad. (2010). Progastriscin: structure, function, and its role in tumor progression. J Mol. Cell Biol. 2: 118-127.

Hessler, S., F. Zheng, S. Hartmann, A. Rittger, S. Lehnert, M. Völkel, M. Nissen, E. Edelmann, P. Saftig, M. Schwake, T. Huth, and C. Alzheimer. (2015). β-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a β-Subunit-Like Fashion. J. Neurosci. 35: 3298-3311.

Kim, D.Y., B.W. Carey, H. Wang, L.A. Ingano, A.M. Binshtok, M.H. Wertz, W.H. Pettingell, P. He, V.M. Lee, C.J. Woolf, and D.M. Kovacs. (2007). BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat. Cell Biol. 9: 755-764.

Richter, C., T. Tanaka, and R.Y. Yada. (1998). Mechanism of activation of the gastric aspartic proteinases: pepsinogen, progastricsin and prochymosin. Biochem. J. 335(Pt3): 481-490.

Steiner, H., M. Than, W. Bode, and C. Haass. (2006). Pore-forming scissors? A first structural glimpse of γ-secretase. Trends Biochem. Sci. 31: 491-493.

Tolia, A., K. Horré, and B. De Strooper. (2008). Transmembrane domain 9 of presenilin determines the dynamic conformation of the catalytic site of γ-secretase. J. Biol. Chem. 283: 19793-19803.

Yan, R., M.J. Bienkowski, M.E. Shuck, H. Miao, M.C. Tory, A.M. Pauley, J.R. Brashier, N.C. Stratman, W.R. Mathews, A.E. Buhl, D.B. Carter, A.G. Tomasselli, L.A. Parodi, R.L. Heinrikson, and M.E. Gurney. (1999). Membrane-anchored aspartyl protease with Alzheimer''s disease β-secretase activity. Nature 402: 533-537.

Examples:

TC#NameOrganismal TypeExample
8.A.32.1.1

β-amyloid cleaving enzyme I of the pepsin/retropepsin-like aspartyl protease superfamily.  BACE1 amplified reconstituted M-currents, altered their voltage dependence, accelerated activation, and slowed deactivation by physical association with channel proteins in a beta-subunit-like fashion (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 promotes BACE1 trimerization and binding of copper ions in vitro. It conducts copper ions through a constricted, partially solvated, axial pore. A central P472 induced kink enables copper ions to alternate between different coordination sites including the prominent C466 and M470 (Bittner et al. 2018).

Animals

BACE1 of Homo sapiens (P56817)

 
8.A.32.1.2

β-secretase 2 of 518 aas, BACE2.

beta-secretase 2 of Homo sapiens

 
8.A.32.1.3

beta-secretase 2 isoform A of 518 aas and 1 or 2 TMSs.  It is responsible for the proteolytic processing of the amyloid precursor protein (APP) (Yan et al. 1999).

β-secretase of Homo sapiens

 
8.A.32.1.4

Pro-gastricsin, PGC of 388 aas.  It shows a more restricted substrate specificity than pepsin A, but shows preferential cleavage at Tyr-|-Xaa bonds (Hassan et al. 2010).  It is a member of the aspartic protease family, including pepsin and chymosin (Richter et al. 1998). It is involved in production of pro-antimicrobial substances in seminal plasma. The crystal structure shows that it is quite similar to that of porcine pepsinogen. The tertiary structure of PGC is bilobal with a large active-site cleft between the lobes. Two aspartyl residues in the center of the cleft, namely Asp32 and Asp215, function as catalytic residues (Hassan et al. 2010).

Pgc of Homo sapiens

 
8.A.32.1.5

Protein aspartic protease in guard cells of 653 aas and 2 TMSs, N- and C-terminal.

Asp prtease of Brassica rapa (field mustard)

 
Examples:

TC#NameOrganismal TypeExample