NDLI: Superstoichiometric binding of L-Phe to phenylalanine hydroxylase from Caenorhabditis elegans: evolutionary implications

Content Provider	Springer Nature Link
Author	Flydal, Marte I. Mohn, Tonje C. Pey, Angel L. Siltberg Liberles, Jessica Teigen, Knut Martinez, Aurora
Copyright Year	2010
Abstract	Phenylalanine hydroxylase (PAH) catalyzes the hydroxylation of L-Phe to L-Tyr. Dysfunctional PAH results in phenylketonuria and mammalian PAH is therefore highly regulated and displays positive cooperativity for L-Phe (Hill coefficient (h) = 2). L-Phe does not bind to the regulatory ACT domain in full-length tetrameric human PAH and cooperativity is elicited by homotropic binding to the catalytic site (Thórólfsson et al. in Biochemistry 41:7573–7585, 2002). PAH from Caenorhabditis elegans (cePAH) is devoid of cooperativity for L-Phe (h = 0.9), and, as shown in this work, structural analysis reveal an additional L-Phe binding site at the regulatory domain of full-length cePAH. This site involves the GA(S)L/ISRP motifs, which are also found in ACT domains of other L-Phe binding proteins, such as prephenate dehydratase. Isothermal titration calorimetry further demonstrated 2 binding sites per subunit for cePAH versus ~1 for hPAH. Steric occlusion of the regulatory site, notably by residues Lys215/Tyr216 from the adjacent catalytic domain, appears to hinder regulatory binding in full-length hPAH. Accordingly, the humanized mutant Q215K/N216Y of cePAH binds ~1.4 L-Phe/subunit. This mutant also displays high catalytic activity and certain positive cooperativity for L-Phe (h = 1.4). Our results support that the acquisition of positive cooperativity in mammalian forms of PAH is accompanied by a closure of the regulatory L-Phe binding site. Concomitantly, the function of the regulatory ACT domain appears to be adapted from amino acid binding to serving the communication of conformational changes among catalytic subunits.
Starting Page	1463
Ending Page	1475
Page Count	13
File Format	PDF
ISSN	09394451
Journal	Amino Acids
Volume Number	39
Issue Number	5
e-ISSN	14382199
Language	English
Publisher	Springer Vienna
Publisher Date	2010-05-18
Publisher Place	Vienna
Access Restriction	Subscribed
Subject Keyword	Allosterism Enzyme regulation Binding stoichiometry Prephenate dehydratase Evolution Neurobiology Proteomics Life Sciences Biochemical Engineering Analytical Chemistry Biochemistry
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Biochemistry Clinical Biochemistry

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