Modelling success stories (3) Goldbeter and Koshland 1981

The third example of this series will be a bit controversial (I was already told so). Understanding its full impact requires more subtle than average understanding of biochemistry and enzyme kinetics, and in particular of the difference between zero and first order kinetics. At least it took me a fair bit of reading and thinking. It will perhaps be easier for you, my bright readers. In 1981, Albert Goldbeter (who will become the “Mr oscillation” of modelling, see his recent book “La vie oscillatoire : Au coeur des rythmes du vivant“) and Daniel Koshland, of “induced-fit” fame, proposed that cascades of coupled interconvertible enzymes could generate ultrasensitive response to an upstream signal. The main body of the work is described in a fairly well cited paper (733 citations according to Google scholar as of 2 July 2013):

Goldbeter A, Koshland DE Jr. An amplified sensitivity arising from covalent modification in biological systems. Proc Natl Acad Sci USA 1981 78(11): 6840-6844. PDF2

Stadtman and Chock had already shown that cascades of such enzymes could generate amplified responses, and if the same substrate was consumed at the different levels, “cooperativity” could appear for the consumption of this substrate in the first order domain (when the enzyme is limiting) (Stadtman and Chock (1977) Proc Natl Acad Sci USA, 74: 2761-2765 and 2766-2770). However Golbeter and Koshland showed that in the zeroth order range (when the substrate is limiting), ultrasensitivity could occur, without the need of multiple inputs at each level. In my opinion this paper is important for at least two reasons. First it described how ultrasensitive (“cooperative”, although nothing cooperate here) behaviours in signalling cascade can appear without mutimeric allosteric assemblies. Second, it predicted the possible existence of MAPK cascades a decade before their discovery (Gomez and Cohen (1991) Nature 353: 170-173). As for the famous Crick and Watson understatement, Golbeter and Koshland land their bomb in the discussion:

“Simple extension of the mathematics shows that the sensitivity can be propagated and enhanced in a multicycle network.”

They go on to add:

“It should be emphasized that the data are not yet available to say with certainty that this device for added sensitivity is actually utilized in biological systems […]”

Indeed. Of course since then, it has been shown with clear certainty that this device is actually utilised in biological systems. Below I show a figure from the Goldbeter and Koshland paper followed by a figure of the first computational model of MAP kinase cascade by Huang and Ferrell (Huang, Ferrell (1996) Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 93: 10078-10083.)