PubMed · 1851963
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R J Lefkowitz. 1991-05-30. Thrombin receptor. Variations on a theme.. https://doi.org/10.1038/351353a0
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The actions of many extracellular stimuli are elicited by complexes of cell surface receptors, heterotrimeric guanine nucleotide-binding proteins (G proteins), and mitogen-activated protein kinase (MAPK) complexes. Analysis of haploid yeast cells and their response to peptide mating pheromones has produced important advances in the understanding of G protein and MAPK signaling mechanisms. Many of the components, their interrelationships, and their regulators were first identified in yeast. Examples include definitive demonstration of a positive signaling role for G protein betagamma subunits, the discovery of a three-tiered structure of the MAPK module, development of the concept of a kinase-scaffold protein, and the discovery of the first regulator of G protein signaling protein. New and powerful genomic, proteomic, and computational approaches available in yeast are beginning to uncover new pathway components and interactions and have revealed their presence in unexpected locations within the cell. This updated Connections Map in the Database of Cell Signaling includes several major revisions to this prototypical signal response pathway.
Sec2 is a reversibly membrane associated multi-domain protein with guanine nucleotide exchange activity towards the yeast Rab-protein Sec4. Both proteins are localized to secretory vesicles destined for exocytosis. We have used transient kinetic methods to show that Sec2 is a highly active exchange factor, in contrast to other proteins previously characterized as Rab exchange factors. With a K(d) value for the Sec2:Sec4.GDP interaction of ca 70 microM and a maximal rate of GDP displacement of ca 15 s(-1), it is 100-1000-fold more effective than other proteins showing exchange activity towards Rabs (MSS4, DSS4, Vps9) and ca tenfold faster than Cdc25 as a Ras specific exchanger, although still 100-fold slower than the fastest systems studied so far, EF-Tu/Ef-Ts and Ran/RCC1. A comparison with other proteins showing Rab exchange activity shows that maximal rates of GDP dissociation catalyzed by Sec2 are orders of magnitude faster. When comparing Sec2 with DSS4, which also acts on Sec4, the difference was particularly dramatic. Another difference is seen in the kinetics of association of GTP with the Sec4:Sec2 complex, a process which is extremely slow for DSS4/MSS4 complexes with cognate Rabs but in the range observed for other GTPase:exchanger complexes for Sec4:Sec2., It is suggested that systems such as Ef-Tu/Ef-Ts and Ran/RCC1 have evolved for maximal possible activity for the interaction between two soluble proteins, whereas other evolutionary constraints which are connected to the spatial and temporal coordination of events in vesicular transport and other regulatory networks have determined the detailed kinetic properties of the other systems.