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Journal article
First structure of full-length mammalian phenylalanine hydroxylase reveals the architecture of an autoinhibited tetramer
Proceedings of the National Academy of Sciences - PNAS, v 113(9), pp 2394-2399
01 Mar 2016
PMID: 26884182
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Improved understanding of the relationship among structure, dynamics, and function for the enzyme phenylalanine hydroxylase (PAH) can lead to needed new therapies for phenylketonuria, the most common inborn error of amino acid metabolism. PAH is a multidomain homo-multimeric protein whose conformation and multimerization properties respond to allosteric activation by the substrate phenylalanine (Phe); the allosteric regulation is necessary to maintain Phe below neurotoxic levels. A recently introduced model for allosteric regulation of PAH involves major domain motions and architecturally distinct PAH tetramers [Jaffe EK, Stith L, Lawrence SH, Andrake M, Dunbrack RL, Jr (2013) Arch Biochem Biophys 530(2):73-82]. Herein, we present, to our knowledge, the first X-ray crystal structure for a full-length mammalian (rat) PAH in an autoinhibited conformation. Chromatographic isolation of a monodisperse tetrameric PAH, in the absence of Phe, facilitated determination of the 2.9 Å crystal structure. The structure of full-length PAH supersedes a composite homology model that had been used extensively to rationalize phenylketonuria genotype-phenotype relationships. Small-angle X-ray scattering (SAXS) confirms that this tetramer, which dominates in the absence of Phe, is different from a Phe-stabilized allosterically activated PAH tetramer. The lack of structural detail for activated PAH remains a barrier to complete understanding of phenylketonuria genotype-phenotype relationships. Nevertheless, the use of SAXS and X-ray crystallography together to inspect PAH structure provides, to our knowledge, the first complete view of the enzyme in a tetrameric form that was not possible with prior partial crystal structures, and facilitates interpretation of a wealth of biochemical and structural data that was hitherto impossible to evaluate.
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Details
- Title
- First structure of full-length mammalian phenylalanine hydroxylase reveals the architecture of an autoinhibited tetramer
- Creators
- Emilia C Arturo - Drexel UniversityKushol Gupta - University of PennsylvaniaAnnie Héroux - Brookhaven National LaboratoryLinda Stith - Temple University Health SystemPenelope J Cross - University of AucklandEmily J Parker - University of AucklandPatrick J Loll - Drexel UniversityEileen K Jaffe - Temple University Health SystemBrookhaven National Lab. (BNL), Upton, NY (United States)
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 113(9), pp 2394-2399
- Publisher
- PNAS
- Grant note
- P30 CA006927 / NCI NIH HHS P41 GM103473 / NIGMS NIH HHS P30CA006927 / NCI NIH HHS P41GM103473 / NIGMS NIH HHS P41 RR012408 / NCRR NIH HHS P41RR012408 / NCRR NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000371204500042
- Scopus ID
- 2-s2.0-84959486007
- Other Identifier
- 991019168063804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology