Science：单个蛋白质拼接可产生多种抗原多肽

信息来源：本站原创　更新时间：2006-9-20 7:19:38
想要理解一些医学基础研究的问题，人们经常要依靠蛋白质序列和编码这个蛋白质的DNA之间直接、线性的关系。实际上，DNA和蛋白质序列的共线性被认为所有遗传密码的基本特征。同一篇报道见：蛋白序列可以和DNA序列不对应
然而，一篇发表在8月7日的Science上的文章发现了一种能被重新组合的蛋白质，因此它与编码它的DNA就不再是共线性的了。完成这篇文章的研究小组来自全球Ludwig癌症研究所布鲁塞尔分所(LICR)和以西雅图为基地的Hutchinson癌症研究中心的科学家。
一段基因的DNA链上，既有编码（蛋白质）DNA序列，也散落着非编码DNA序列。制造蛋白质的第一步是将整个基因序列忠实地转录为RNA序列。而后就是RNA被拼接的过程。这些散落非编码序列被移除，编码序列便集合成线性方式从而形成了RNA翻译为蛋白质的模版。
这篇文章的通讯作者，LICR的Benoit  Van  den  Eynde博士说：“到目前为止，仅RNA拼接这一事实的存在就打破了DNA和蛋白质共线性这种说法。这项新研究表明蛋白质也有拼接现象，有时甚至产生的蛋白质片段或多肽以与亲本相反的方向拼接在一起。根据Van  den  Eynde博士的说法，这种新颖的现象常发生在一种名为”抗原加工“的生理过程中，抗原加工会产生抗原多肽，而这会让靶细胞被标上“红旗”标志，以便免疫系统将其摧毁。
当T淋巴细胞识别出细胞表面存在抗原多肽时，免疫系统便将其认为异种细胞，并开始攻击，这些异种细胞包括肿瘤细胞，病毒感染的细胞和来源于捐赠人的细胞。抗原们由蛋白酶体的成员加工产生，蛋白酶体也是细胞机制的一部分。这些蛋白酶体将外来蛋白切割成多肽，并将其陈列在细胞表面供CD8+  T淋巴细胞发挥识别和摧毁作用。然而，比利时/美国的一个研究小组发现蛋白酶体还可以拼接这些肽段，拼接的方向与编码这些蛋白质的DNA模版链方向相反。这使得来源于一种蛋白的抗原有可能达到数千种之多。
第一个人类癌症特异抗原就是在LICR布鲁塞尔分所鉴定得到的，这使抗原特异的癌症疫苗得以研发，目前有关这种疫苗的临床实验已在世界范围内蓬勃开展起来。这项研究描述了单一蛋白可产生数目众多的抗原多肽这一现象的机制，由此可扩大癌症和感染性疾病的肽类疫苗的应用。
Understanding medical research problems often relies on the direct, linear relationship between the sequence of a protein and the DNA encoding that protein. In fact, colinearity of DNA and protein sequences is thought to be a fundamental feature of the universal genetic code. However, a paper published today in Science by a team from the Brussels Branch of the global Ludwig Institute for Cancer Research (LICR) and the Seattle-based Fred Hutchinson Cancer Research Center (FHCRC), shows that a protein can be rearranged so that it is no longer colinear with its encoding DNA.
Genes have stretches of (protein) coding DNA sequences interspersed with stretches of non-coding DNA sequences. The first step in making the protein is the faithful transcription of the entire gene s sequence into an RNA sequence. The RNA is then  spliced   such that the non-coding sequences are removed and the coding sequences are assembled in a linear fashion to form the template for translation from RNA to protein.
"Until now it was thought that colinearity of DNA and protein sequences was only interrupted by RNA splicing," says LICR s Dr. Benoit Van den Eynde, the study s senior author. "This new study shows that protein splicing also occurs, and may even result in protein fragments, or peptides, being spliced together in the order opposite to that which occurs in the parental protein."
According to Dr. Van den Eynde, this novel phenomenon occurs during the physiological function of  antigen processing,   which produces antigenic peptides; the  red flags   that mark cells for destruction by the immune system.
The immune system attacks  foreign   cells - be they tumor cells, virally infected, or donated by another person - when T lymphocytes recognize antigenic peptides displayed on the cell surface. The antigens are created by  proteasomes,   components of the cell machinery that cut foreign proteins into peptides that are then displayed on the cell surface for recognition and destruction by CD8+ T lymphocytes. However, the Belgium/USA team has found that proteasomes can also splice the peptide fragments together in a reverse order to that encoded by the protein s DNA sequence template. This takes the possible number of antigens from any one protein into potentially thousands of sequence configurations.
The sequence of the first human cancer-specific antigen, which was identified at the LICR Brussels Branch, has allowed the development of antigen-specific cancer vaccines that are in clinical trials around the world. This study describes a mechanism that significantly extends the number of antigenic peptides that can be produced from a single protein, and therefore widens the applicability of peptide vaccines against cancer and infectious diseases.