دورية أكاديمية
Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation
| العنوان: | Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation |
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| المؤلفون: | Bueno-Carrasco, M. Teresa, Cuéllar, Jorge, Flydal, Marte I., Santiago, César, Kråkenes, Trond-André, Kleppe, Rune, López-Blanco, José R., Marcilla, Miguel, Teigen, Knut, Alvira, Sara, Chacón, Pablo, Martínez, Aurora, Valpuesta, José M. |
| المساهمون: | Ministerio de Ciencia e Innovación (España), Research Council of Norway, Western Norway Regional Health Authority, Bueno-Carrasco, M. Teresa, Cuéllar, Jorge, Flydal, Marte I., Santiago, César, Kråkenes, Trond-André, López-Blanco, José R., Marcilla, Miguel, Teigen, Knut, Alvira, Sara, Chacón, Pablo, Martinez, Aurora, Valpuesta, José M. |
| بيانات النشر: | Springer Nature |
| سنة النشر: | 2022 |
| المجموعة: | Digital.CSIC (Consejo Superior de Investigaciones Científicas / Spanish National Research Council) |
| الوصف: | 16 pags, 7 figs . -- The online version contains supplementary movie1: https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-021-27657-y/MediaObjects/41467_2021_27657_MOESM3_ESM.mp4Test ; 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. ; 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. ; Peer reviewed |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2041-1723 |
| العلاقة: | #PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105872GB-I00/ES/CHAPERONAS MOLECULARES: ACTORES PRINCIPALES EN LA HOMEOSTASIS PROTEICA/; Nature communications; Publisher's version; https://doi.org/10.1038/s41467-021-27657-yTest; Sí; Nature Communications 13 (1): 74 (2022); http://hdl.handle.net/10261/259541Test; http://dx.doi.org/10.13039/501100004837Test; 2-s2.0-85122891415; https://api.elsevier.com/content/abstract/scopus_id/85122891415Test |
| DOI: | 10.1038/s41467-021-27657-y |
| DOI: | 10.13039/501100004837 |
| الإتاحة: | https://doi.org/10.1038/s41467-021-27657-y10.13039/501100004837Test http://hdl.handle.net/10261/259541Test https://api.elsevier.com/content/abstract/scopus_id/85122891415Test |
| حقوق: | open |
| رقم الانضمام: | edsbas.3EF8EA56 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 20411723 |
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| DOI: | 10.1038/s41467-021-27657-y |