Transient exposure of a buried phosphorylation site in an autoinhibited protein

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Standard

Transient exposure of a buried phosphorylation site in an autoinhibited protein. / Orioli, Simone; Henning Hansen, Carl G.; Lindorff-Larsen, Kresten.

I: Biophysical Journal, Bind 121, Nr. 1, 2022, s. 91-101.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Orioli, S, Henning Hansen, CG & Lindorff-Larsen, K 2022, 'Transient exposure of a buried phosphorylation site in an autoinhibited protein', Biophysical Journal, bind 121, nr. 1, s. 91-101. https://doi.org/10.1016/j.bpj.2021.11.2890

APA

Orioli, S., Henning Hansen, C. G., & Lindorff-Larsen, K. (2022). Transient exposure of a buried phosphorylation site in an autoinhibited protein. Biophysical Journal, 121(1), 91-101. https://doi.org/10.1016/j.bpj.2021.11.2890

Vancouver

Orioli S, Henning Hansen CG, Lindorff-Larsen K. Transient exposure of a buried phosphorylation site in an autoinhibited protein. Biophysical Journal. 2022;121(1):91-101. https://doi.org/10.1016/j.bpj.2021.11.2890

Author

Orioli, Simone ; Henning Hansen, Carl G. ; Lindorff-Larsen, Kresten. / Transient exposure of a buried phosphorylation site in an autoinhibited protein. I: Biophysical Journal. 2022 ; Bind 121, Nr. 1. s. 91-101.

Bibtex

@article{6e1f46192f1e4b96be88cd5036934873,

title = "Transient exposure of a buried phosphorylation site in an autoinhibited protein",

abstract = "Autoinhibition is a mechanism used to regulate protein function, often by making functional sites inaccessible through the interaction with a cis-acting inhibitory domain. Such autoinhibitory domains often display a substantial degree of structural disorder when unbound, and only become structured in the inhibited state. These conformational dynamics make it difficult to study the structural origin of regulation, including effects of regulatory post-translational modifications. Here, we study the autoinhibition of the Dbl Homology domain in the protein Vav1 by the so-called acidic inhibitory domain. We use molecular simulations to study the process by which a mostly unstructured inhibitory domain folds upon binding and how transient exposure of a key buried tyrosine residue makes it accessible for phosphorylation. We show that the inhibitory domain, which forms a helix in the bound and inhibited stated, samples helical structures already before binding and that binding occurs via a molten-globule-like intermediate state. Together, our results shed light on key interactions that enable the inhibitory domain to sample a finely tuned equilibrium between an inhibited and a kinase-accessible state.",

author = "Simone Orioli and {Henning Hansen}, {Carl G.} and Kresten Lindorff-Larsen",

note = "Publisher Copyright: {\textcopyright} 2021 Biophysical Society",

year = "2022",

doi = "10.1016/j.bpj.2021.11.2890",

language = "English",

volume = "121",

pages = "91--101",

journal = "Biophysical Journal",

issn = "0006-3495",

publisher = "Cell Press",

number = "1",

}

RIS

TY - JOUR

T1 - Transient exposure of a buried phosphorylation site in an autoinhibited protein

AU - Orioli, Simone

AU - Henning Hansen, Carl G.

AU - Lindorff-Larsen, Kresten

PY - 2022

Y1 - 2022

N2 - Autoinhibition is a mechanism used to regulate protein function, often by making functional sites inaccessible through the interaction with a cis-acting inhibitory domain. Such autoinhibitory domains often display a substantial degree of structural disorder when unbound, and only become structured in the inhibited state. These conformational dynamics make it difficult to study the structural origin of regulation, including effects of regulatory post-translational modifications. Here, we study the autoinhibition of the Dbl Homology domain in the protein Vav1 by the so-called acidic inhibitory domain. We use molecular simulations to study the process by which a mostly unstructured inhibitory domain folds upon binding and how transient exposure of a key buried tyrosine residue makes it accessible for phosphorylation. We show that the inhibitory domain, which forms a helix in the bound and inhibited stated, samples helical structures already before binding and that binding occurs via a molten-globule-like intermediate state. Together, our results shed light on key interactions that enable the inhibitory domain to sample a finely tuned equilibrium between an inhibited and a kinase-accessible state.

AB - Autoinhibition is a mechanism used to regulate protein function, often by making functional sites inaccessible through the interaction with a cis-acting inhibitory domain. Such autoinhibitory domains often display a substantial degree of structural disorder when unbound, and only become structured in the inhibited state. These conformational dynamics make it difficult to study the structural origin of regulation, including effects of regulatory post-translational modifications. Here, we study the autoinhibition of the Dbl Homology domain in the protein Vav1 by the so-called acidic inhibitory domain. We use molecular simulations to study the process by which a mostly unstructured inhibitory domain folds upon binding and how transient exposure of a key buried tyrosine residue makes it accessible for phosphorylation. We show that the inhibitory domain, which forms a helix in the bound and inhibited stated, samples helical structures already before binding and that binding occurs via a molten-globule-like intermediate state. Together, our results shed light on key interactions that enable the inhibitory domain to sample a finely tuned equilibrium between an inhibited and a kinase-accessible state.

U2 - 10.1016/j.bpj.2021.11.2890

DO - 10.1016/j.bpj.2021.11.2890

M3 - Journal article

C2 - 34864046

AN - SCOPUS:85121749337

VL - 121

SP - 91

EP - 101

JO - Biophysical Journal

JF - Biophysical Journal

SN - 0006-3495

IS - 1

ER -

ID: 289306713

Niels Bohr Institutet