Abstract
Perturbed Ca(2+) homeostasis is a common molecular consequence of familial Alzheimer's disease-linked presenilin mutations. We report here the molecular interaction of the large hydrophilic loop region of presenilin 2 (PS2) with sorcin, a penta-EF-hand Ca(2+)-binding protein that serves as a modulator of the ryanodine receptor intracellular Ca(2+) channel. The association of endogenous sorcin and PS2 was demonstrated in cultured cells and human brain tissues. Membrane-associated sorcin and a subset of the functional PS2 complexes were co-localized to a novel subcellular fraction that is distinctively positive for calcineurin B. Sorcin was found to interact with PS2 endoproteolytic fragments but not full-length PS2, and the sorcin/PS2 interaction was greatly enhanced by treatment with the Ca(2+) ionophore A23187. Our findings reveal a molecular link between PS2 and intracellular Ca(2+) channels (i.e. ryanodine receptor) and substantiate normal and/or pathological roles of PS2 in intracellular Ca(2+) homeostasis.
Highlights
Half of early-onset familial Alzheimer’s disease (FAD)1 is associated with mutations in genes encoding two homologous proteins, presenilin 1 (PS1) and presenilin 2 (PS2) [1]
Our results reveal a molecular link between PS2 and intracellular Ca2ϩ channels, suggesting that sorcin is involved in the role of PS2 in intracellular Ca2ϩ homeostasis
We asked whether the protein sorcin, which has previously been shown to interact with the N-terminal region of synexin [47], might interact with the PS2 loop
Summary
Half of early-onset familial Alzheimer’s disease (FAD)1 is associated with mutations in genes encoding two homologous proteins, presenilin 1 (PS1) and presenilin 2 (PS2) [1]. We report here the molecular interaction of the large hydrophilic loop region of presenilin 2 (PS2) with sorcin, a penta-EF-hand Ca2؉-binding protein that serves as a modulator of the ryanodine receptor intracellular Ca2؉ channel. Mycsorcin was co-immunoprecipitated by ␣PS2Loop, indicating that Myc-sorcin interacts with endogenous PS2 C-terminal (loop) fragments (PS2-CTF) (Fig. 1C).
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