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Identification of BACE1 cleavage sites in human voltage-gated sodium channel beta 2 subunit

Gersbacher, Manuel T, Kim, Doo Yeon, Bhattacharyya, Raja, Kovacs, Dora M·2010·Molecular Neurodegeneration
DOI 10.1186/1750-1326-5-61PMC PMC3022600
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Abstract

Background: The voltage-gated sodium channel β2 subunit (Navβ2) is a physiological substrate of BACE1 (β-site APP cleaving enzyme) and γ-secretase, two proteolytic enzymes central to Alzheimer's disease pathogenesis. Previously, we have found that the processing of Navβ2 by BACE1 and γ-secretase regulates sodium channel metabolism in neuronal cells. In the current study we identified the BACE1 cleavage sites in human Navβ2. Results: We found a major (147-148 L↓M, where ↓ indicates the cleavage site) and a minor (144145 L↓Q) BACE1 cleavage site in the extracellular domain of human Navβ2 using a cell-free BACE1 cleavage assay followed by mass spectrometry. Next, we introduced two different double mutations into the identified major BACE1 cleavage site in human Navβ2: 147LM/VI and 147LM/AA. Both mutations dramatically decreased the cleavage of human Navβ2 by endogenous BACE1 in cell-free BACE1 cleavage assays. Neither of the two mutations affected subcellular localization of Navβ2 as confirmed by confocal fluorescence microscopy and subcellular fractionation of cholesterol-rich domains. Finally, wildtype and mutated Navβ2 were expressed along BACE1 in B104 rat neuroblastoma cells. In spite of α-secretase still actively cleaving the mutant proteins, Navβ2 cleavage products decreased by ~50% in cells expressing Navβ2 (147LM/VI) and ~75% in cells expressing Navβ2 (147LM/AA) as compared to cells expressing wildtype Navβ2. Conclusion: We identified a major (147-148 L↓M) and a minor (144-145 L↓Q) BACE1 cleavage site in human Navβ2. Our in vitro and cell-based results clearly show that the 147-148 L↓M is the major BACE1 cleavage site in human Navβ2. These findings expand our understanding of the role of BACE1 in voltage-gated sodium channel metabolism.

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  • BACE1 has been implicated in regulation of sodium channel metabolism in neuronal cells via its cleavage of Navβ2.

    “BACE1 has also been implicated in regulation of sodium channel metabolism in neuronal cells, via its cleavage of voltage‐gated sodium channel β2 subunit (Navβ2).”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [32]

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Metadata

Authors
Gersbacher, M. T., Kim, D. Y., Bhattacharyya, R., & Kovacs, D. M.
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2010-12
Volume
5
Issue
1
ISSN
1750-1326
DOI
10.1186/1750-1326-5-61
PMC
PMC3022600
Cited by
32
References
1
Language
en
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