Solution structure of the antiapoptotic protein bcl-2
Solution structure of the antiapoptotic protein bcl-2
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DOI：
10.1073/pnas.041619798
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发表时间：
2001-03-13
影响因子：
11.1
通讯作者：
Fesik, SW
中科院分区：
文献类型：
--
作者：
Petros, AM;Medek, A;Fesik, SW
Bcl-2的两种异构体的结构不同的两个氨基酸已被确定通过NMR光谱。由于野生型Bcl-2在溶液中表现不佳，因此通过使用Bcl-2/Bcl-x（L）嵌合体来确定结构，其中Bcl-2的部分推定的非结构化环被Bcl-x（L）的缩短环取代。这些嵌合蛋白与野生型蛋白相比具有低pi并且是可溶的。两种Bcl-2同种型的结构由6个α-螺旋组成，表面上具有疏水沟，类似于对同源蛋白Bcl-x（L）观察到的疏水沟。Bcl-2结构与Bcl-x（L）结构的比较表明，尽管整体折叠相同，但结合沟的结构拓扑和静电势存在差异。虽然Bcl-2的两种同种型的结构实际上是相同的，但在蛋白质结合来自促凋亡Bad蛋白的25个残基的肽和来自促凋亡巴克蛋白的16个残基的肽的能力方面观察到差异。这些结果表明，Bcl-2中的疏水结合沟存在细微差异，这可能转化为两种亚型抗凋亡活性的差异。
The structures of two isoforms of Bcl-2 that differ by two amino acids have been determined by NMR spectroscopy. Because wildtype Bcl-2 behaved poorly in solution, the structures were determined by using Bcl-2/Bcl-x(L) chimeras in which part of the putative unstructured loop of Bcl-2 was replaced with a shortened loop from Bcl-x(L). These chimeric proteins have a low pi compared with the wild-type protein and are soluble. The structures of the two Bcl-2 isoforms consist of 6 alpha -helices with a hydrophobic groove on the surface similar to that observed for the homologous protein, Bcl-x(L). Comparison of the Bcl-2 structures to that of Bcl-x(L) shows that although the overall fold is the same, there are differences in the structural topology and electrostatic potential of the binding groove. Although the structures of the two isoforms of Bcl-2 are virtually identical, differences were observed in the ability of the proteins to bind to a 25-residue peptide from the proapoptotic Bad protein and a 16-residue peptide from the proapoptotic Bak protein. These results suggest that there are subtle differences in the hydrophobic binding groove in Bcl-2 that may translate into differences in antiapoptotic activity for the two isoforms.