Golgi anti-apoptotic proteins are highly conserved ion channels that affect apoptosis and cell migration.
Golgi anti-apoptotic proteins are highly conserved ion channels that affect apoptosis and cell migration.
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DOI：
10.1074/jbc.m115.637306
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发表时间：
2015-05-01
期刊：
影响因子：
--
通讯作者：
Smith GL
中科院分区：
文献类型：
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作者：
Carrara G;Saraiva N;Parsons M;Byrne B;Prole DL;Taylor CW;Smith GL
背景：GAAP调节细胞内钙流、细胞迁移和凋亡。结果：GAAP形成阳离子选择性通道，并鉴定了与其离子导电特性相关的残基。结论：在孔内的突变表明，GAAP对细胞凋亡和迁移的影响是分开的。重要性：GAAP的孔区域的表征提供了对这种新颖且高度保守的离子通道的作用机制的深入了解。高尔基体抗凋亡蛋白（GAAP）是在高尔基体中表达的多跨膜蛋白，并且能够同源寡聚化。它们在整个真核生物中高度保守，并且存在于一些原核生物和正痘病毒中。在真核生物中，GAAP调节细胞内钙含量，抑制细胞凋亡，促进细胞粘附和迁移。本文提供的数据表明，纯化的病毒GAAP（vGAAP）和人Bax抑制剂1形成离子通道，并且来自骆驼痘病毒的vGAAP对阳离子具有选择性。vGAAP的突变，包括最近解决的相关细菌蛋白BsYetJ的结构中保守的一些残基，改变了通道的电导率（E207 Q和D219 N）和离子选择性（E207 Q）。残基Glu-207或-178的突变降低了GAAP对细胞迁移和粘附的影响，而不影响对凋亡的保护。与此相反，突变的Asp-219废除的抗凋亡活性的GAAP，但不影响其对细胞迁移和粘附。这些结果表明，GAAP是离子通道，并确定有助于离子传导孔的残基，并独立地影响凋亡、细胞粘附和迁移。
Background: GAAPs regulate intracellular Ca2+ fluxes, cell migration, and apoptosis. Results: GAAP forms a cation-selective channel, and residues involved in its ion-conducting properties were identified. Conclusion: Mutations within the pore demonstrate that GAAP effects on apoptosis and migration are separable. Significance: Characterization of the pore region of GAAP provides insight into the mechanism of action of this novel and highly conserved ion channel. Golgi anti-apoptotic proteins (GAAPs) are multitransmembrane proteins that are expressed in the Golgi apparatus and are able to homo-oligomerize. They are highly conserved throughout eukaryotes and are present in some prokaryotes and orthopoxviruses. Within eukaryotes, GAAPs regulate the Ca2+ content of intracellular stores, inhibit apoptosis, and promote cell adhesion and migration. Data presented here demonstrate that purified viral GAAPs (vGAAPs) and human Bax inhibitor 1 form ion channels and that vGAAP from camelpox virus is selective for cations. Mutagenesis of vGAAP, including some residues conserved in the recently solved structure of a related bacterial protein, BsYetJ, altered the conductance (E207Q and D219N) and ion selectivity (E207Q) of the channel. Mutation of residue Glu-207 or -178 reduced the effects of GAAP on cell migration and adhesion without affecting protection from apoptosis. In contrast, mutation of Asp-219 abrogated the anti-apoptotic activity of GAAP but not its effects on cell migration and adhesion. These results demonstrate that GAAPs are ion channels and define residues that contribute to the ion-conducting pore and affect apoptosis, cell adhesion, and migration independently.