Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation

María Teresa Bueno-Carrasco; Jorge Cuéllar; Marte I Flydal; César Santiago; Trond-André Kråkenes; Rune Kleppe; José R López-Blanco; Miguel Marcilla; Knut Teigen; Sara  Alvira-De-Celis; Pablo Chacón; Aurora Martinez; José M Valpuesta

doi:10.1038/s41467-021-27657-y

Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation

María Teresa Bueno-Carrasco
, Jorge Cuéllar^*
, Marte I Flydal
, César Santiago
, Trond-André Kråkenes
, Rune Kleppe
, José R López-Blanco
, Miguel Marcilla
, Knut Teigen
, Sara Alvira-De-Celis
, Pablo Chacón
, Aurora Martinez^*
, José M Valpuesta^*

^*Corresponding author for this work

Bristol Neuroscience

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines, and its dysfunction leads to DA deficiency and parkinsonisms. Inhibition by catecholamines and reactivation by S40 phosphorylation are key regulatory mechanisms of TH activity and conformational stability. We used Cryo-EM to determine the structures of full-length human TH without and with DA, and the structure of S40 phosphorylated TH, complemented with biophysical and biochemical characterizations and molecular dynamics simulations. TH presents a tetrameric structure with dimerized regulatory domains that are separated 15 Å from the catalytic domains. Upon DA binding, a 20-residue α-helix in the flexible N-terminal tail of the regulatory domain is fixed in the active site, blocking it, while S40-phosphorylation forces its egress. The structures reveal the molecular basis of the inhibitory and stabilizing effects of DA and its counteraction by S40-phosphorylation, key regulatory mechanisms for homeostasis of DA and TH.

Original language	English
Article number	74
Number of pages	17
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27657-y
Publication status	Published - 10 Jan 2022

Bibliographical note

Funding Information:
This research was supported by the grant PID2019-105872GB-I00/AEI/10.13039/ 501100011033 from the Spanish Ministry of Science and Innovation to J.M.V. and J.C. as well as FRIMEDBIO (261826) from the Research Council of Norway to A.M.; the Western Norway Regional Health Authorities (912246 to A.M. and 912264 to R.K.), the K.G.

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© 2022, The Author(s).

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Bueno-Carrasco, M. T., Cuéllar, J., Flydal, M. I., Santiago, C., Kråkenes, T.-A., Kleppe, R., López-Blanco, J. R., Marcilla, M., Teigen, K., Alvira-De-Celis, S., Chacón, P., Martinez, A., & Valpuesta, J. M. (2022). Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation. Nature Communications, 13(1), Article 74. https://doi.org/10.1038/s41467-021-27657-y

@article{fe5cf0db29f24200b7a2ea0196c7dbfe,

title = "Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation",

abstract = "Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines, and its dysfunction leads to DA deficiency and parkinsonisms. Inhibition by catecholamines and reactivation by S40 phosphorylation are key regulatory mechanisms of TH activity and conformational stability. We used Cryo-EM to determine the structures of full-length human TH without and with DA, and the structure of S40 phosphorylated TH, complemented with biophysical and biochemical characterizations and molecular dynamics simulations. TH presents a tetrameric structure with dimerized regulatory domains that are separated 15 {\AA} from the catalytic domains. Upon DA binding, a 20-residue α-helix in the flexible N-terminal tail of the regulatory domain is fixed in the active site, blocking it, while S40-phosphorylation forces its egress. The structures reveal the molecular basis of the inhibitory and stabilizing effects of DA and its counteraction by S40-phosphorylation, key regulatory mechanisms for homeostasis of DA and TH.",

author = "Bueno-Carrasco, \{Mar{\'i}a Teresa\} and Jorge Cu{\'e}llar and Flydal, \{Marte I\} and C{\'e}sar Santiago and Trond-Andr{\'e} Kr{\aa}kenes and Rune Kleppe and L{\'o}pez-Blanco, \{Jos{\'e} R\} and Miguel Marcilla and Knut Teigen and Sara Alvira-De-Celis and Pablo Chac{\'o}n and Aurora Martinez and Valpuesta, \{Jos{\'e} M\}",

note = "Funding Information: This research was supported by the grant PID2019-105872GB-I00/AEI/10.13039/ 501100011033 from the Spanish Ministry of Science and Innovation to J.M.V. and J.C. as well as FRIMEDBIO (261826) from the Research Council of Norway to A.M.; the Western Norway Regional Health Authorities (912246 to A.M. and 912264 to R.K.), the K.G. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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doi = "10.1038/s41467-021-27657-y",

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Bueno-Carrasco, MT, Cuéllar, J, Flydal, MI, Santiago, C, Kråkenes, T-A, Kleppe, R, López-Blanco, JR, Marcilla, M, Teigen, K, Alvira-De-Celis, S, Chacón, P, Martinez, A & Valpuesta, JM 2022, 'Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation', Nature Communications, vol. 13, no. 1, 74. https://doi.org/10.1038/s41467-021-27657-y

TY - JOUR

T1 - Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation

AU - Bueno-Carrasco, María Teresa

AU - Cuéllar, Jorge

AU - Flydal, Marte I

AU - Santiago, César

AU - Kråkenes, Trond-André

AU - Kleppe, Rune

AU - López-Blanco, José R

AU - Marcilla, Miguel

AU - Teigen, Knut

AU - Alvira-De-Celis, Sara

AU - Chacón, Pablo

AU - Martinez, Aurora

AU - Valpuesta, José M

N1 - Funding Information: This research was supported by the grant PID2019-105872GB-I00/AEI/10.13039/ 501100011033 from the Spanish Ministry of Science and Innovation to J.M.V. and J.C. as well as FRIMEDBIO (261826) from the Research Council of Norway to A.M.; the Western Norway Regional Health Authorities (912246 to A.M. and 912264 to R.K.), the K.G. Publisher Copyright: © 2022, The Author(s).

PY - 2022/1/10

Y1 - 2022/1/10

N2 - Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines, and its dysfunction leads to DA deficiency and parkinsonisms. Inhibition by catecholamines and reactivation by S40 phosphorylation are key regulatory mechanisms of TH activity and conformational stability. We used Cryo-EM to determine the structures of full-length human TH without and with DA, and the structure of S40 phosphorylated TH, complemented with biophysical and biochemical characterizations and molecular dynamics simulations. TH presents a tetrameric structure with dimerized regulatory domains that are separated 15 Å from the catalytic domains. Upon DA binding, a 20-residue α-helix in the flexible N-terminal tail of the regulatory domain is fixed in the active site, blocking it, while S40-phosphorylation forces its egress. The structures reveal the molecular basis of the inhibitory and stabilizing effects of DA and its counteraction by S40-phosphorylation, key regulatory mechanisms for homeostasis of DA and TH.

AB - Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines, and its dysfunction leads to DA deficiency and parkinsonisms. Inhibition by catecholamines and reactivation by S40 phosphorylation are key regulatory mechanisms of TH activity and conformational stability. We used Cryo-EM to determine the structures of full-length human TH without and with DA, and the structure of S40 phosphorylated TH, complemented with biophysical and biochemical characterizations and molecular dynamics simulations. TH presents a tetrameric structure with dimerized regulatory domains that are separated 15 Å from the catalytic domains. Upon DA binding, a 20-residue α-helix in the flexible N-terminal tail of the regulatory domain is fixed in the active site, blocking it, while S40-phosphorylation forces its egress. The structures reveal the molecular basis of the inhibitory and stabilizing effects of DA and its counteraction by S40-phosphorylation, key regulatory mechanisms for homeostasis of DA and TH.

U2 - 10.1038/s41467-021-27657-y

DO - 10.1038/s41467-021-27657-y

M3 - Article (Academic Journal)

C2 - 35013193

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 74

ER -

Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation

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