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Intrinsically disordered linkers control tethered kinases via effective concentration

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Intrinsically disordered linkers control tethered kinases via effective concentration. / Dyla, Mateusz; Kjaergaard, Magnus.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, No. 35, 09.2020.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Dyla, M & Kjaergaard, M 2020, 'Intrinsically disordered linkers control tethered kinases via effective concentration', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 35. https://doi.org/10.1073/pnas.2006382117

APA

Dyla, M., & Kjaergaard, M. (2020). Intrinsically disordered linkers control tethered kinases via effective concentration. Proceedings of the National Academy of Sciences of the United States of America, 117(35). https://doi.org/10.1073/pnas.2006382117

CBE

Dyla M, Kjaergaard M. 2020. Intrinsically disordered linkers control tethered kinases via effective concentration. Proceedings of the National Academy of Sciences of the United States of America. 117(35). https://doi.org/10.1073/pnas.2006382117

MLA

Dyla, Mateusz and Magnus Kjaergaard. "Intrinsically disordered linkers control tethered kinases via effective concentration". Proceedings of the National Academy of Sciences of the United States of America. 2020. 117(35). https://doi.org/10.1073/pnas.2006382117

Vancouver

Dyla M, Kjaergaard M. Intrinsically disordered linkers control tethered kinases via effective concentration. Proceedings of the National Academy of Sciences of the United States of America. 2020 Sep;117(35). https://doi.org/10.1073/pnas.2006382117

Author

Dyla, Mateusz ; Kjaergaard, Magnus. / Intrinsically disordered linkers control tethered kinases via effective concentration. In: Proceedings of the National Academy of Sciences of the United States of America. 2020 ; Vol. 117, No. 35.

Bibtex

@article{e3874e62ffe84267ba6cc1d9c3dbbc4b,
title = "Intrinsically disordered linkers control tethered kinases via effective concentration",
abstract = "Kinase specificity is crucial to the fidelity of signaling 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 intracomplex reactions depend on the link between enzyme and substrate. Here we show that the kinetics of tethered kinases follow a Michaelis-Menten-like dependence on effective concentration. We find that phosphorylation kinetics scale with the length of the intrinsically disordered linkers that join the enzyme and substrate but that the scaling differs between substrates. Steady-state kinetics can only partially predict rates of tethered reactions as product release may obscure the rate of phosphotransfer. Our results suggest that changes in signaling complex architecture not only enhance the rates of phosphorylation reactions but may also alter the relative substrate usage. This suggests a mechanism for how scaffolding proteins can allosterically modify the output from a signaling pathway.",
author = "Mateusz Dyla and Magnus Kjaergaard",
year = "2020",
month = sep,
doi = "10.1073/pnas.2006382117",
language = "English",
volume = "117",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "35",

}

RIS

TY - JOUR

T1 - Intrinsically disordered linkers control tethered kinases via effective concentration

AU - Dyla, Mateusz

AU - Kjaergaard, Magnus

PY - 2020/9

Y1 - 2020/9

N2 - Kinase specificity is crucial to the fidelity of signaling 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 intracomplex reactions depend on the link between enzyme and substrate. Here we show that the kinetics of tethered kinases follow a Michaelis-Menten-like dependence on effective concentration. We find that phosphorylation kinetics scale with the length of the intrinsically disordered linkers that join the enzyme and substrate but that the scaling differs between substrates. Steady-state kinetics can only partially predict rates of tethered reactions as product release may obscure the rate of phosphotransfer. Our results suggest that changes in signaling complex architecture not only enhance the rates of phosphorylation reactions but may also alter the relative substrate usage. This suggests a mechanism for how scaffolding proteins can allosterically modify the output from a signaling pathway.

AB - Kinase specificity is crucial to the fidelity of signaling 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 intracomplex reactions depend on the link between enzyme and substrate. Here we show that the kinetics of tethered kinases follow a Michaelis-Menten-like dependence on effective concentration. We find that phosphorylation kinetics scale with the length of the intrinsically disordered linkers that join the enzyme and substrate but that the scaling differs between substrates. Steady-state kinetics can only partially predict rates of tethered reactions as product release may obscure the rate of phosphotransfer. Our results suggest that changes in signaling complex architecture not only enhance the rates of phosphorylation reactions but may also alter the relative substrate usage. This suggests a mechanism for how scaffolding proteins can allosterically modify the output from a signaling pathway.

U2 - 10.1073/pnas.2006382117

DO - 10.1073/pnas.2006382117

M3 - Journal article

C2 - 32817491

VL - 117

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 35

ER -