Human and viral Golgi anti-apoptotic protein (GAAP); a structural and functional study of its mechanism of action

细胞的生死受到非常严格的监管，是包括人类在内的多细胞生物体生命的重要组成部分。程序性细胞死亡，称为细胞凋亡，在许多过程中都是至关重要的。例如，在发育过程中，许多细胞必须死亡才能形成适当的器官结构。细胞死亡也会发生在生物体的整个生命过程中，这对消除功能不正常的细胞至关重要，包括癌细胞或被病毒感染的细胞。我们发现了一种新的人类蛋白质，称为h-GAAP，它控制细胞死亡，在从植物到人类和痘病毒的进化过程中一直是保守的。我们研究h-GAAP是因为痘苗病毒，用于根除天花的疫苗，会产生一种非常相似的蛋白质，称为v-GAAP。我们打算确定h-GAAP和v-GAAP的结构，并确定GAAP的哪些部分是需要的：i)将其定向到其在细胞内的特定位置，称为高尔基复合体；ii)介导其与一种名为IP3R的细胞蛋白质的相互作用，该蛋白质调节钙离子和iii)保护细胞免受凋亡。H-GAAP在高尔基复合体中的位置特别有趣，因为高尔基体并不经常与控制细胞死亡联系在一起。增加我们对这一重要蛋白质的了解是很重要的，因为h-GAAP可能在发育、癌症和传染病中发挥作用。我们还将研究v-GAAP在痘苗病毒感染过程中的作用，并比较v-GAAP和其他痘苗病毒蛋白抑制细胞凋亡的作用。

The life or death of a cell is very strictly regulated and is an essential component in the life of multicellular organisms, including humans. Programmed cell death, called apoptosis, is critical in many processes. For instance, during development, many cells must die to create properly formed organ structures. Cell death also occurs throughout an organism?s life and is crucial to eliminate cells that are functioning incorrectly, including cancer cells or cells infected by a virus. We discovered a new human protein, termed h-GAAP, which controls cell death and that has been conserved during evolution all the way from plants to humans and poxviruses. We studied h-GAAP because vaccinia virus, the vaccine used to eradicate smallpox, makes a very similar protein called v-GAAP.We intend to determine the structure of h-GAAP and v-GAAP, and identify the parts of GAAPs that are needed to i) direct it to its particular location within the cell called the Golgi complex, ii) mediate its interaction with a cell protein called IP3R that regulates calcium and iii) protect cells from apoptosis. The location of h-GAAP in the Golgi complex is particularly interesting because the Golgi is not often associated with the control of cell death. It is important to increase our understanding of this important protein, because h-GAAP is likely to have a role in development, cancer and infectious diseases. We will also study the role of v-GAAP during vaccinia virus infection and compare the role of v-GAAP and other vaccinia virus proteins that inhibit apoptosis.