Transient exposure of a buried phosphorylation site in an autoinhibited protein
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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
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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
N1 - Publisher Copyright: © 2021 Biophysical Society
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