The role of DNA in the mechanism of NF kappa B dimer formation: crystal structures of the dimerization domains of the p50 and p65 subunits
The role of DNA in the mechanism of NF kappa B dimer formation: crystal structures of the dimerization domains of the p50 and p65 subunits
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DOI：
10.1016/s0969-2126(97)00293-1
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发表时间：
1997-11-15
期刊：
影响因子：
5.7
通讯作者：
Ghosh, G
中科院分区：
文献类型：
--
作者：
Huang, DB;Huxford, T;Ghosh, G
背景资料：转录因子的rel/NF κ B家族的成员在快速细胞应答的调节中起着至关重要的作用，例如对抗感染或对细胞应激反应所需的那些。该蛋白质家族的成员形成具有不同二聚化亲和力的同源和异源二聚体。它们共有一个称为rel同源区（RHR）的结构基序，其中C-末端三分之一介导蛋白质二聚化。rel/NF κ B家族成员p50和p65以其DNA结合的同源二聚体形式的晶体结构已被解析。这些结构表明，来自p50和p65的二聚化结构域的残基参与DNA结合，并且DNA-蛋白质和蛋白质二聚化表面形成一个连续的重叠界面。我们希望调查的贡献的DNA NF κ B B二聚化和确定的机制，为选择性协会的rel/NF κ B家族肽到转录活性dimeres.Results：我们在这里报告的晶体结构的二聚化结构域的小鼠p50和p65在2.2埃和2.0埃分辨率，分别。这两种结构的比较表明，保守的氨基酸的变化在三个位置是负责在其二聚体接口的差异。靶DNA的存在并不改变任何显着mart.Conclusions的蛋白质的二聚体接口：这两个结构表明，rel/NF κ B B家族的转录因子使用只有少数保守的变化，在其氨基酸序列形成一个主机的二聚体与不同的亲和力二聚化。在对应于鼠p50的254、267和307的位置处的氨基酸充当所观察到的二聚化亲和力差异的主要决定因素。来自二聚化结构域的与DNA接触的带电荷氨基酸侧链在DNA结合和游离状态下均保持相似的构象，因此，不需要主要的结构重排来使这些残基与DNA接触。
Background: Members of the rel/NF kappa B family of transcription factors play a vital role in the regulation of rapid cellular responses, such as those required to fight infection or react to cellular stress. Members of this family of proteins form home-and heterodimers with differing affinities for dimerization. They share a structural motif known as the rel homology region (RHR), the C-terminal one third of which mediates protein dimerization. Crystal structures of the rel/NF kappa B family members p50 and p65 in their DNA-bound homodimeric form have been solved. These structures showed that the residues from the dimerization domains of both p50 and p65 participate in DNA binding and that the DNA-protein and protein dimerization surfaces form one continuous overlapping interface. We desired to investigate the contribution of DNA to NF kappa B dimerization and to identify the mechanism for the selective association of rel/NF kappa B family peptides into transcriptionally active dimers.Results: We report here the crystal structures of the dimerization domains of murine p50 and p65 at 2.2 Angstrom and 2.0 Angstrom resolution, respectively. A comparison of these two structures suggests that conservative amino acid changes at three positions are responsible for the differences in their dimer interfaces. The presence of the target DNA does not change the dimer interface of either protein in any significant manner.Conclusions: These two structures suggest that the rel/NF kappa B family of transcription factors use only a few conservative changes in their amino acid sequences to form a host of dimers with varying affinities for dimerization. Amino acids at positions corresponding to 254, 267, and 307 of murine p50, function as primary determinants for the observed differences in dimerization affinity. The DNA-contacting charged amino acid sidechains from the dimerization domains are held in a similar conformation in both the DNA-bound and free states, therefore, no major structural rearrangement is required to bring these residues into contact with the DNA.