Xue Bin, Brown Celeste J, Dunker A Keith, Uversky Vladimir N
Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA.
Biochim Biophys Acta. 2013 Apr;1834(4):725-38. doi: 10.1016/j.bbapap.2013.01.012. Epub 2013 Jan 22.
Proteins of the p53 family are expressed in vertebrates and in some invertebrate species. The main function of these proteins is to control and regulate cell cycle in response to various cellular signals, and therefore to control the organism's development. The regulatory functions of the p53 family members originate mostly from their highly-conserved and well-structured DNA-binding domains. Many human diseases (including various types of cancer) are related to the missense mutations within this domain. The ordered DNA-binding domains of the p53 family members are surrounded by functionally important intrinsically disordered regions. In this study, substitution rates and propensities in different regions of p53 were analyzed. The analyses revealed that the ordered DNA-binding domain is conserved, whereas disordered regions are characterized by high sequence diversity. This diversity was reflected both in the number of substitutions and in the types of substitutions to which each amino acid was prone. These results support the existence of a positive correlation between protein intrinsic disorder and sequence divergence during the evolutionary process. This higher sequence divergence provides strong support for the existence of disordered regions in p53 in vivo for if they were structured, they would evolve at similar rates as the rest of the protein.
p53家族蛋白在脊椎动物和一些无脊椎动物物种中均有表达。这些蛋白的主要功能是响应各种细胞信号来控制和调节细胞周期，进而控制生物体的发育。p53家族成员的调节功能主要源于其高度保守且结构良好的DNA结合结构域。许多人类疾病（包括各种类型的癌症）都与该结构域内的错义突变有关。p53家族成员有序的DNA结合结构域被功能重要的内在无序区域所包围。在本研究中，分析了p53不同区域的替换率和倾向。分析表明，有序的DNA结合结构域是保守的，而无序区域的特点是具有高度的序列多样性。这种多样性既体现在替换的数量上，也体现在每个氨基酸易于发生的替换类型上。这些结果支持了在进化过程中蛋白质内在无序与序列分歧之间存在正相关。这种更高的序列分歧有力地支持了p53体内无序区域的存在，因为如果它们是结构化的，其进化速率将与蛋白质的其他部分相似。
