Nakamoto Tokumasa
Department of Biochemistry and Molecular Biology, The University of Chicago, 5801 S. Ellis Ave, Chicago, IL 60637, USA.
Gene. 2007 Nov 15;403(1-2):1-5. doi: 10.1016/j.gene.2007.08.006. Epub 2007 Aug 25.
An extension of our unique accessibility hypothesis for the initiation of protein synthesis is proposed following a review of the initiation of protein synthesis. The E. coli model initiation sequence generated by computer from 68 initiation sequences and the eukaryotic consensus initiation sequence derived by non-computer analysis of 211 initiation sequences do not contain a specific base in any position; they are only assigned preferred bases. The initiation site, in other words, is a varied sequence of preferred bases and its sequence is non-unique. This indicates that the ribosomal recognition of the initiation site may be the result of multiple interactions that are cooperative and cumulative and typical of multisubstrate enzymes. Because of this characteristic, the model of multisubstrate enzymes with broad substrate specificity is proposed as a paradigm for the initiation of protein synthesis. As predicted by this model, changes in the leader and downstream sequences that improve the agreement with the preferred base sequence do indeed enhance the rate of protein synthesis. The eukaryotic/prokaryotic hybrid studies show a considerable overlap in the specificities of the two groups of ribosomes. The scanning of the mRNA from the 5'-end postulated by the scanning hypothesis is not a necessary step since eukaryotic ribosomes are able to bind to internal mRNA sites and initiate synthesis. Our unique accessibility hypothesis, which is extended by coupling cooperative and cumulative specificity in ribosomal function, is referred to for brevity as the cumulative specificity hypothesis. The hypothesis actually postulates a selective accessibility and cooperative-cumulative specificity mechanism; it is able to account for the behavior of both eukaryotic and prokaryotic initiation of protein synthesis. From another perspective, the hypothesis can be regarded as providing a mechanism that enables ribosomes to recognize the IS in the absence of a unique initiation sequence.
在对蛋白质合成起始进行综述之后，我们提出了一个关于蛋白质合成起始的独特可及性假说的扩展内容。通过计算机从68个起始序列生成的大肠杆菌模型起始序列，以及通过对211个起始序列进行非计算机分析得出的真核生物共有起始序列，在任何位置都不包含特定碱基；它们只是被赋予了偏好碱基。换句话说，起始位点是偏好碱基的可变序列，其序列并非唯一。这表明核糖体对起始位点的识别可能是多种相互作用的结果，这些相互作用具有协同性和累积性，是多底物酶的典型特征。由于这一特性，提出具有广泛底物特异性的多底物酶模型作为蛋白质合成起始的范例。正如该模型所预测的，前导序列和下游序列中与偏好碱基序列一致性提高的变化确实会增强蛋白质合成的速率。真核生物/原核生物杂交研究表明，两组核糖体的特异性有相当大的重叠。扫描假说所假定的从5'端对mRNA的扫描不是一个必要步骤，因为真核生物核糖体能够结合到mRNA内部位点并起始合成。我们独特的可及性假说通过将核糖体功能中的协同和累积特异性相结合进行扩展，为简洁起见，被称为累积特异性假说。该假说实际上假定了一种选择性可及性和协同累积特异性机制；它能够解释真核生物和原核生物蛋白质合成起始的行为。从另一个角度来看，该假说可以被视为提供了一种机制，使核糖体能够在没有唯一起始序列的情况下识别起始位点。
