Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin

6 pags., 3 figs.

Detalles Bibliográficos
Autores: Flydal, M.I., Alcorlo, Martín, Johannessen, F.G., Martínez-Caballero, Siseth, Skjærven, L., Fernández-Leiro, Rafael, Martínez, A., Hermoso, Juan A.
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/206729
Acceso en línea:http://hdl.handle.net/10261/206729
Access Level:acceso abierto
Palabra clave:Human phenylalanine hydroxylase
Phenylketonuria
X-ray crystallography
Cryo-EM
Allosteric regulation
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spelling Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterinFlydal, M.I.Alcorlo, MartínJohannessen, F.G.Martínez-Caballero, Siseth Skjærven, L.Fernández-Leiro, RafaelMartínez, A.Hermoso, Juan A.Human phenylalanine hydroxylasePhenylketonuriaX-ray crystallographyCryo-EMAllosteric regulation6 pags., 3 figs.Phenylalanine hydroxylase (PAH) is a key enzyme in the catabo-lism of phenylalanine, and mutations in this enzyme cause phenylketonuria (PKU), a genetic disorder that leads to brain damage and mental retardation if untreated. Some patients benefit from supplementation with a synthetic formulation of the cofactor tetrahydrobiopterin (BH) that partly acts as a pharmacological chaperone. Here we present structures of full-length human PAH (hPAH) both unbound and complexed with BH in the precatalytic state. Crystal structures, solved at 3.18-Å resolution, show the interactions between the cofactor and PAH, explaining the negative regulation exerted by BH. BH forms several H-bonds with the N-terminal autoregulatory tail but is far from the catalytic Fe. Upon BH binding a polar and salt-bridge interaction network links the three PAH domains, explaining the stability conferred by BH. Importantly, BH binding modulates the interaction between subunits, providing information about PAH allostery. Moreover, we also show that the cryo-EM structure of hPAH in absence of BH reveals a highly dynamic conformation for the tetramers. Structural analyses of the hPAH:BH subunits revealed that the substrate-induced movement of Tyr138 into the active site could be coupled to the displacement of BH from the precatalytic toward the active conformation, a molecular mechanism that was supported by site-directed mutagenesis and targeted molecular dynamics simulations. Finally, comparison of the rat and human PAH structures show that hPAH is more dynamic, which is related to amino acid substitutions that enhance the flexibility of hPAH and may increase the susceptibility to PKU-associated mutations.The work was supported by grants from the MICINN Spanish Ministry of Research, Innovation & Universities BFU2017-90030-P (to J.A.H.) and BFU2017-87316 (to R.F.-L.); programs Forny (248889/O30) and FRIMEDBIO (261826) from the Research Council of Norway (to A.M.); the Western Norway Regional Health Authorities (Helse Vest Projects 911959 to M.I.F. and 912246 to A.M.); and the K.G. Jebsen foundation (to M.I.F. and A.M.), the staff from ALBA synchrotron facility (Barcelona) and the European Synchrotron Radiation Facility (ESRF)National Academy of Sciences (U.S.)Ministerio de Ciencia, Innovación y Universidades (España)Research Council of NorwayWestern Norway Regional Health AuthorityALBA SynchrotronEuropean Synchrotron Radiation FacilityConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020192020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/206729reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/BFU2017-90030-Pinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/BFU2017-87316http://dx.doi.org/10.1073/pnas.1902639116Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2067292026-05-22T06:33:51Z
dc.title.none.fl_str_mv Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin
title Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin
spellingShingle Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin
Flydal, M.I.
Human phenylalanine hydroxylase
Phenylketonuria
X-ray crystallography
Cryo-EM
Allosteric regulation
title_short Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin
title_full Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin
title_fullStr Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin
title_full_unstemmed Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin
title_sort Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin
dc.creator.none.fl_str_mv Flydal, M.I.
Alcorlo, Martín
Johannessen, F.G.
Martínez-Caballero, Siseth
Skjærven, L.
Fernández-Leiro, Rafael
Martínez, A.
Hermoso, Juan A.
author Flydal, M.I.
author_facet Flydal, M.I.
Alcorlo, Martín
Johannessen, F.G.
Martínez-Caballero, Siseth
Skjærven, L.
Fernández-Leiro, Rafael
Martínez, A.
Hermoso, Juan A.
author_role author
author2 Alcorlo, Martín
Johannessen, F.G.
Martínez-Caballero, Siseth
Skjærven, L.
Fernández-Leiro, Rafael
Martínez, A.
Hermoso, Juan A.
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Research Council of Norway
Western Norway Regional Health Authority
ALBA Synchrotron
European Synchrotron Radiation Facility
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Human phenylalanine hydroxylase
Phenylketonuria
X-ray crystallography
Cryo-EM
Allosteric regulation
topic Human phenylalanine hydroxylase
Phenylketonuria
X-ray crystallography
Cryo-EM
Allosteric regulation
description 6 pags., 3 figs.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/206729
url http://hdl.handle.net/10261/206729
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/BFU2017-90030-P
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/BFU2017-87316
http://dx.doi.org/10.1073/pnas.1902639116
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv National Academy of Sciences (U.S.)
publisher.none.fl_str_mv National Academy of Sciences (U.S.)
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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