蛋白质的局部结构与功能的进化
文献类型：学位论文
| 作者 | 李功华 |
| 学位类别 | 博士 |
| 答辩日期 | 2009-07 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 黄京飞 |
| 关键词 | 蛋白质局部结构 CMASA DNase I-like 超家族 |
| 学位专业 | 动物学 |
| 中文摘要 | 蛋白质行使功能时主要是由一些重要的局部结构执行.一方面蛋白质局部结构的差异导致了同一超家族功能的多样性.另一方面,局部结构的相似性导致不同fold具有相似的功能. 因此,研究蛋白质局部结构与功能的进化对理解蛋白质结构与功能的关系具有重要意义. 而要研究蛋白质局部结构与功能的进化首先要解决一个方法学上的问题，即确定蛋白质局部结构的相似性与差异性。尽管已有一些方法用来比较两个蛋白质局部结构之间的相似性，但每种方法都存在一定的缺陷。因此我们新开发了一种基于蛋白质连接矩阵的局部结构比对算法(Contact MAtrix based local Structural Alignment,简称CMASA). 结果显示CMASA具有很高的专一性(0.96)与敏感性(0.86)。比现有的蛋白质局部结构比对方法的专一性和敏感性要高。不仅如此CMASA的执行效率也非常高。利用CMASA算法，我们对整个PDB数据库进行了功能注释，检测到了166个新的酶以及相应的活性中心(p<0.0001). 因此CMASA是一个高专一性和敏感性以及快速的蛋白质局部结构比对算法，这个新算法会对理解蛋白质局部结构与功能的关系，基于蛋白质局部结构的药物设计等具有重要意义。现在CMASA已经做成了基于邮件的服务器，网址为: http://www.kiz.ac.cn/other1/CMASA/CMASA.htm。 为了研究新功能产生的结构机制，本研究挑选了DNase I-like 超家族作为例子。DNase I-like 超家族包括核酸酶，磷酸酶以及NO转运蛋白。尽管超家族成员的每个功能都研究的较清楚，但超家族进化的结构机制并不清楚。通过结构与功能的分析，本研究发现４个局部结构的差异决定了不同蛋白质的专一性。其中磷酸酶和NO转运蛋白因为一个局部结构的物理阻断作用而无法和DNA结合，而其它专一性差异也因为这四个局部结构的物理或化学的差异导致，有趣的是我们还发现与功能和专一性相关的保守残基都处在这四个局部结构中或附近。最后我们根据局部结构与功能的变化关系提出了蛋白质局部结构与功能进化的渐进性进化模型。本研究将有助于理解同一超家族成员如何行使不同的功能，以及蛋白质局部结构的变化如何导致功能的进化。 |
| 英文摘要 | Generally, the protein holds its function by protein local structure. So the protein local structural differences will result in the functional differences. In the other hand, the similar local structure will result in the similar function even when the proteins located in different folds. So it will be helpful to understand the relationship between the protein structure and function by research the evolution of the protein local structure and function. However, to research the evolution of the protein local structure, we must firstly solve a methodology problem for detecting the local structure similarity. Although there are some algorithms developed to solve this problem, each algorithm has its own limitation. So we developed a new algorithm called CMASA (Contact MAtrix based local Structural Alignment algorithm) to detect protein local structural similarity. The results show that CMASA is high accuracy (0.96) and high sensitivity (0.86), which is better than the current local structural similarity method. Rather more, CMASA is fast enough for large-scale functional annotation. Then, we apply this algorithm to annotate the non-redundant PDB and hit at least 166 novel non-redundant enzyme catalytic sites which failed to be annotated in CSA. The success of this new algorithm will be greatly help for understanding the relationship between the protein local structure and the function, and can be used in drug design. Now we have developed a mail-based server and can available at http://www.kiz.ac.cn/other1/CMASA/CMASA.htm. To investigate the structural mechanism of the new functional evolution, we select the DNase I-like superfamily，which contains nuclease, phosphatase and NO transporter. Although each family member is well understood, the relationship between structure and specificity in the superfamily is unclear. Using structural and functional analysis, we identified four key local structures determine the different functions. Phosphatase and NO transporter can not bind DNA because of the physical block of a local structure. Other specificities are also result from the chemical or physical differences of the four local structures. Interesting, further sequence analysis shows that the conserved amino acids are located or near in the four key local structures. Thus, a stepwise model was proposed to explain the evolutionary relationship between the local structure and function. This study will be helpful for understanding how a single fold can hold different functions and how the protein local structural change result into functional evolution in a superfamily. |
| 语种 | 中文 |
| 公开日期 | 2013-04-24 |
| 源URL | [http://159.226.149.42:8088/handle/152453/7402]  |
| 专题 | 昆明动物研究所_结构生物信息学 |
| 推荐引用方式 GB/T 7714 | 李功华. 蛋白质的局部结构与功能的进化[D]. 北京. 中国科学院研究生院. 2009. |
入库方式： OAI收割
来源：昆明动物研究所
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