期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：6
页码：2473-2478
DOI：10.1073/pnas.0906885107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Multisite covalent modification of proteins is omnipresent in eukaryotic cells. A well-known example is the mitogen-activated protein kinase (MAPK) cascade where, in each layer of the cascade, a protein is phosphorylated at two sites. It has long been known that the response of a MAPK pathway strongly depends on whether the enzymes that modify the protein act processively or distributively. A distributive mechanism, in which the enzyme molecules have to release the substrate molecules in between the modification of the two sites, can generate an ultrasensitive response and lead to hysteresis and bistability. We study by Green's Function Reaction Dynamics (GFRD), a stochastic scheme that makes it possible to simulate biochemical networks at the particle level in time and space, a dual phosphorylation cycle in which the enzymes act according to a distributive mechanism. We find that the response of this network can differ dramatically from that predicted by a mean-field analysis based on the chemical rate equations. In particular, rapid rebindings of the enzyme molecules to the substrate molecules after modification of the first site can markedly speed up the response and lead to loss of ultrasensitivity and bistability. In essence, rapid enzyme-substrate rebindings can turn a distributive mechanism into a processive mechanism. We argue that slow ADP release by the enzymes can protect the system against these rapid rebindings, thus enabling ultrasensitivity and bistability.
