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Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain

Published on Apr 1, 2016in Scientific Reports4.01
· DOI :10.1038/srep23748
Dipali Patel11
Estimated H-index: 11
(University of Oxford),
Jolanta Kopec14
Estimated H-index: 14
(SGC: Structural Genomics Consortium)
+ 2 AuthorsWyatt W. Yue25
Estimated H-index: 25
(SGC: Structural Genomics Consortium)
Abstract
The multi-domain enzyme phenylalanine hydroxylase (PAH) catalyzes the hydroxylation of dietary I-phenylalanine (Phe) to I-tyrosine. Inherited mutations that result in PAH enzyme deficiency are the genetic cause of the autosomal recessive disorder phenylketonuria. Phe is the substrate for the PAH active site, but also an allosteric ligand that increases enzyme activity. Phe has been proposed to bind, in addition to the catalytic domain, a site at the PAH N-terminal regulatory domain (PAH-RD), to activate the enzyme via an unclear mechanism. Here we report the crystal structure of human PAH-RD bound with Phe at 1.8 A resolution, revealing a homodimer of ACT folds with Phe bound at the dimer interface. This work delivers the structural evidence to support previous solution studies that a binding site exists in the RD for Phe, and that Phe binding results in dimerization of PAH-RD. Consistent with our structural observation, a disease-associated PAH mutant impaired in Phe binding disrupts the monomer:dimer equilibrium of PAH-RD. Our data therefore support an emerging model of PAH allosteric regulation, whereby Phe binds to PAH-RD and mediates the dimerization of regulatory modules that would bring about conformational changes to activate the enzyme.
  • References (50)
  • Citations (20)
References50
Newest
#1Shengnan Zhang (University of Texas Health Science Center at San Antonio)H-Index: 6
#2Paul F. Fitzpatrick (University of Texas Health Science Center at San Antonio)H-Index: 34
#1Sarah Wettstein (Boston Children's Hospital)H-Index: 1
#2Jarl Underhaug (University of Bergen)H-Index: 13
Last.Nenad Blau (Boston Children's Hospital)H-Index: 56
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#1Thomas J. McCorvie (SGC: Structural Genomics Consortium)H-Index: 11
#2Jolanta Kopec (SGC: Structural Genomics Consortium)H-Index: 14
Last.Wyatt W. Yue (SGC: Structural Genomics Consortium)H-Index: 25
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#1Kenneth M. Roberts (University of Texas Health Science Center at San Antonio)H-Index: 7
#2Crystal A. Khan (University of Texas Health Science Center at San Antonio)H-Index: 4
Last.Paul F. Fitzpatrick (University of Texas Health Science Center at San Antonio)H-Index: 34
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#1Eric J. M. Lang (Cant.: University of Canterbury)H-Index: 3
#2Penelope J. Cross (Cant.: University of Canterbury)H-Index: 7
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#2Kenneth M. Roberts (University of Texas Health Science Center at San Antonio)H-Index: 7
Last.Paul F. FitzpatrickH-Index: 34
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#1Ania C. Muntau (LMU: Ludwig Maximilian University of Munich)H-Index: 35
#2João Leandro (University of Lisbon)H-Index: 7
Last.Søren W. Gersting (LMU: Ludwig Maximilian University of Munich)H-Index: 14
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#1Francesco Montalbano (University of Lisbon)H-Index: 4
#2João Leandro (University of Lisbon)H-Index: 7
Last.Pedro M. P. Gois (University of Lisbon)H-Index: 21
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#1Shengnan Zhang (University of Texas Health Science Center at San Antonio)H-Index: 6
#2Tao Huang (University of Texas Health Science Center at San Antonio)H-Index: 8
Last.Paul F. Fitzpatrick (University of Texas Health Science Center at San Antonio)H-Index: 34
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Cited By20
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#1Rasmus Scheller (UCPH: University of Copenhagen)H-Index: 1
#2Amelie Stein (UCPH: University of Copenhagen)H-Index: 16
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#1Kirill A. Konovalov (HKUST: Hong Kong University of Science and Technology)
#2Wei Wang (HKUST: Hong Kong University of Science and Technology)H-Index: 2
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#1D. S. Froese (Boston Children's Hospital)H-Index: 2
#2Jola Kopec (SGC: Structural Genomics Consortium)H-Index: 3
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#2Jola Kopec (SGC: Structural Genomics Consortium)H-Index: 3
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