Ko Emily Ray, Ko Dennis, Chen Carolyn, Lipsick Joseph S
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5324, USA.
Mol Cancer. 2008 Oct 7;7:77. doi: 10.1186/1476-4598-7-77.
The c-Myb protein is a transcriptional regulator initially identified by homology to the v-Myb oncoprotein, and has since been implicated in human cancer. The most highly conserved portion of the c-Myb protein is the DNA-binding domain which consists of three imperfect repeats. Many other proteins contain one or more Myb-related domains, including a number of proteins that do not bind directly to DNA. We performed a phylogenetic analysis of diverse classes of Myb-related domains and discovered a highly conserved patch of acidic residues common to all Myb-related domains. These acidic residues are positioned in the first of three alpha-helices within each of the three repeats that comprise the c-Myb DNA-binding domain. Interestingly, these conserved acidic residues are present on a surface of the protein which is distinct from that which binds to DNA. Alanine mutagenesis revealed that the acidic patch of the third c-Myb repeat is essential for transcriptional activity, but neither for nuclear localization nor DNA-binding. Instead, these acidic residues are required for efficient chromatin binding and interaction with the histone H4 N-terminal tail.
c-Myb蛋白是一种转录调节因子，最初是通过与v-Myb癌蛋白的同源性鉴定出来的，此后被认为与人类癌症有关。c-Myb蛋白中最保守的部分是由三个不完全重复序列组成的DNA结合结构域。许多其他蛋白质含有一个或多个Myb相关结构域，包括一些不直接与DNA结合的蛋白质。我们对不同类别的Myb相关结构域进行了系统发育分析，发现了所有Myb相关结构域共有的一个高度保守的酸性残基区域。这些酸性残基位于构成c-Myb DNA结合结构域的三个重复序列中每个重复序列的三个α-螺旋中的第一个。有趣的是，这些保守的酸性残基位于蛋白质的一个表面，该表面与结合DNA的表面不同。丙氨酸诱变表明，第三个c-Myb重复序列的酸性区域对转录活性至关重要，但对核定位和DNA结合均不重要。相反，这些酸性残基是有效结合染色质和与组蛋白H4 N末端尾巴相互作用所必需的。
