Semple Jennifer I, Vavouri Tanya, Lehner Ben
EMBL-CRG Systems Biology Unit, Centre for Genomic Regulation (CRG), UPF, Dr, Aiguader 88, Barcelona 08003, Spain.
BMC Syst Biol. 2008 Jan 2;2:1. doi: 10.1186/1752-0509-2-1.
The functions of a eukaryotic cell are largely performed by multi-subunit protein complexes that act as molecular machines or information processing modules in cellular networks. An important problem in systems biology is to understand how, in general, these molecular machines respond to perturbations.
In yeast, genes that inhibit growth when their expression is reduced are strongly enriched amongst the subunits of multi-subunit protein complexes. This applies to both the core and peripheral subunits of protein complexes, and the subunits of each complex normally have the same loss-of-function phenotypes. In contrast, genes that inhibit growth when their expression is increased are not enriched amongst the core or peripheral subunits of protein complexes, and the behaviour of one subunit of a complex is not predictive for the other subunits with respect to over-expression phenotypes.
We propose the principle that the overall activity of a protein complex is in general robust to an increase, but not to a decrease in the expression of its subunits. This means that whereas phenotypes resulting from a decrease in gene expression can be predicted because they cluster on networks of protein complexes, over-expression phenotypes cannot be predicted in this way. We discuss the implications of these findings for understanding how cells are regulated, how they evolve, and how genetic perturbations connect to disease in humans.
真核细胞的功能很大程度上由多亚基蛋白质复合物执行，这些复合物在细胞网络中充当分子机器或信息处理模块。系统生物学中的一个重要问题是总体上理解这些分子机器如何响应扰动。
在酵母中，表达降低时抑制生长的基因在多亚基蛋白质复合物的亚基中高度富集。这适用于蛋白质复合物的核心亚基和外周亚基，并且每个复合物的亚基通常具有相同的功能丧失表型。相比之下，表达增加时抑制生长的基因在蛋白质复合物的核心或外周亚基中并不富集，并且就过表达表型而言，复合物的一个亚基的行为不能预测其他亚基的行为。
我们提出这样一个原则，即蛋白质复合物的总体活性通常对其亚基表达的增加具有鲁棒性，但对其亚基表达的减少则不然。这意味着虽然基因表达降低导致的表型可以预测，因为它们聚集在蛋白质复合物网络上，但过表达表型不能以这种方式预测。我们讨论了这些发现对于理解细胞如何被调控、如何进化以及基因扰动如何与人类疾病相关的意义。
