Deletion mutational analysis of BMRP, a pro-apoptotic protein that binds to Bcl-2
Deletion mutational analysis of BMRP, a pro-apoptotic protein that binds to Bcl-2
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DOI：
10.1007/s11010-011-0729-1
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发表时间：
2011-05-01
影响因子：
4.3
通讯作者：
Gonzalez-Garcia, Maribel
中科院分区：
文献类型：
--
作者：
Malladi, Srinivas;Parsa, Kishore V. L.;Gonzalez-Garcia, Maribel
Bcl-2是Bcl-2蛋白家族的抗凋亡成员，其保护细胞免于由多种刺激诱导的凋亡。蛋白质BMRP（MRPL 41）被鉴定为Bcl-2结合伴侣，并显示具有促凋亡活性。我们进行了缺失突变分析，以确定参与Bcl-2/BMRP相互作用的Bcl-2和BMRP结构域，以及介导其促凋亡活性的BMRP区域。这些研究的结果表明，Bcl-2的BH 4结构域和其中心区域包括其BH 1，BH 2和BH 3结构域都是其与BMRP相互作用所必需的。发现Bcl-2的环区和跨膜结构域对于这种相互作用是不稳定的。不与BMRP相互作用的Bcl-2缺失突变体先前被证明是功能失活的。BMRP蛋白的缺失分析将其与Bcl-2相互作用所需的BMRP区域限定在蛋白的氨基末端三分之二（氨基酸残基1-92）。在BMRP（1-92）截短蛋白的任一末端的进一步缺失导致缺乏与Bcl-2的结合。用BMRP缺失突变体进行的功能研究表明，该蛋白的细胞死亡诱导结构域主要位于其氨基末端的三分之二内。与Bcl-2相互作用所需的BMRP区域与蛋白质的细胞死亡诱导活性非常相关，表明BMRP诱导细胞死亡的一种可能机制是通过结合并阻断Bcl-2的抗凋亡活性。
Bcl-2 is an anti-apoptotic member of the Bcl-2 family of proteins that protects cells from apoptosis induced by a large variety of stimuli. The protein BMRP (MRPL41) was identified as a Bcl-2 binding partner and shown to have pro-apoptotic activity. We have performed deletion mutational analyses to identify the domain(s) of Bcl-2 and BMRP that are involved in the Bcl-2/BMRP interaction, and the region(s) of BMRP that mediate its pro-apoptotic activity. The results of these studies indicate that both the BH4 domain of Bcl-2 and its central region encompassing its BH1, BH2, and BH3 domains are required for its interaction with BMRP. The loop region and the transmembrane domain of Bcl-2 were found to be dispensable for this interaction. The Bcl-2 deletion mutants that do not interact with BMRP were previously shown to be functionally inactive. Deletion analyses of the BMRP protein delimited the region of BMRP needed for its interaction with Bcl-2 to the amino-terminal two-thirds of the protein (amino acid residues 1-92). Further deletions at either end of the BMRP(1-92) truncated protein resulted in lack of binding to Bcl-2. Functional studies performed with BMRP deletion mutants suggest that the cell death-inducing domains of the protein reside mainly within its amino-terminal two-thirds. The region of BMRP required for the interaction with Bcl-2 is very relevant for the cell death-inducing activity of the protein, suggesting that one possible mechanism by which BMRP induces cell death is by binding to and blocking the anti-apoptotic activity of Bcl-2.