2020
DOI: 10.1101/2020.04.04.023713
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Intrinsically disordered linkers control tethered kinases via effective concentration

Abstract: Kinase specificity is crucial to the fidelity of signalling pathways, yet many pathways use the same kinases to achieve widely different effects. Specificity arises in part from the enzymatic domain, but also from the physical tethering of kinases to their substrates.Such tethering can occur via protein interaction domains in the kinase or via anchoring and scaffolding proteins, and can drastically increase the kinetics of phosphorylation.However, we do not know how such intra-complex reactions depend on the l… Show more

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Cited by 7 publications
(7 citation statements)
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“…However, there was no apparent difference in the kinetics of the regulatory T286/T287 autophosphorylation that occurs between the subunits of a holoenzyme. While this result seemed counterintuitive at first glance, (i) it is predicted by simple Michaelis-Menten kinetics (Dyla and Kjaergaard, 2020), although (ii) simple Michaelis-Menten kinetics should not necessarily be expected for this autophosphorylation reaction. When T286 is presented as an exogenous substrate on a peptide, its Km is ~10 µM (Coultrap et al, 2010); with this Km and with 2 versus 1 mM substrate concentration, Michaelis-Menten kinetics predicts reaction speeds of 99.50% vs 99.01% of Vmax, i.e.…”
Section: Holoenzyme Expansion and Autophosphorylation Kineticsmentioning
confidence: 82%
“…However, there was no apparent difference in the kinetics of the regulatory T286/T287 autophosphorylation that occurs between the subunits of a holoenzyme. While this result seemed counterintuitive at first glance, (i) it is predicted by simple Michaelis-Menten kinetics (Dyla and Kjaergaard, 2020), although (ii) simple Michaelis-Menten kinetics should not necessarily be expected for this autophosphorylation reaction. When T286 is presented as an exogenous substrate on a peptide, its Km is ~10 µM (Coultrap et al, 2010); with this Km and with 2 versus 1 mM substrate concentration, Michaelis-Menten kinetics predicts reaction speeds of 99.50% vs 99.01% of Vmax, i.e.…”
Section: Holoenzyme Expansion and Autophosphorylation Kineticsmentioning
confidence: 82%
“…It is increasingly clear that cellular signaling relies on tethered reactions (3,19,50,51), and studies have shown how tethering can increase the rate of these intramolecular reactions (20,21). A feature of tethered reactions by immune receptors and many other membrane-confined reactions is that they are intermolecular.…”
Section: Discussionmentioning
confidence: 99%
“…In contrast to previously studied tethered reactions (20,21,23), in which the enzyme tethers directly to the substrate, the situation is more complicated for immune receptors because the enzyme tethers to a receptor but acts in trans on a different membrane substrate (Fig. 1 A).…”
Section: Introductionmentioning
confidence: 86%
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“…Our work attempts to bridge this gap, connecting submolecular states with the kinetics that provide inputs for models of the signaling cascade. Although the coarse granularity omits many details, such as sequencedependent persistence lengths (62), we join a growing body of modeling efforts (63,64) at the granularity between particles representing individual proteins and particles representing individual atoms, which has been particularly fruitful for intrinsically disordered domains (10)(11)(12)22,65).…”
Section: Discussionmentioning
confidence: 99%