Interdomain Conformational Changes Provide Allosteric Regulation en Route to ChorismateThis work was supported by New Zealand Marsden Fund Grant UOC1105, the Biomolecular Interaction Centre, and the University of Canterbury High Performance Computing. The authors declare that they have no conflicts of interest with the contents of this article.♦♦This article was selected as a Paper of the Week

• Published in: The Journal of biological chemistry Vol. 291; no. 42; pp. 21836 - 21847
• Main Authors: Nazmi, Ali Reza, Lang, Eric J.M., Bai, Yu, Allison, Timothy M., Othman, Mohamad H., Panjikar, Santosh, Arcus, Vickery L., Parker, Emily J.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2016
• Subjects: allosteric regulation; aromatic amino acid; Bacillus; chorismate mutase; crystal structure; DAHPS; inhibition mechanism; multifunctional enzyme; shikimate; X-ray scattering; chorismate mutase; shikimate; inhibition mechanism; X-ray scattering; DAHPS; multifunctional enzyme; Bacillus; crystal structure; allosteric regulation; aromatic amino acid
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.741637

Multifunctional proteins play a variety of roles in metabolism. Here, we examine the catalytic function of the combined 3-deoxy-d-arabino heptulosonate-7-phosphate synthase (DAH7PS) and chorismate mutase (CM) from Geobacillus sp. DAH7PS operates at the start of the biosynthetic pathway for aromatic metabolites, whereas CM operates in a dedicated branch of the pathway for the biosynthesis of amino acids tyrosine and phenylalanine. In line with sequence predictions, the two catalytic functions are located in distinct domains, and these two activities can be separated and retain functionality. For the full-length protein, prephenate, the product of the CM reaction, acts as an allosteric inhibitor for the DAH7PS. The crystal structure of the full-length protein with prephenate bound and the accompanying small angle x-ray scattering data reveal the molecular mechanism of the allostery. Prephenate binding results in the tighter association between the dimeric CM domains and the tetrameric DAH7PS, occluding the active site and therefore disrupting DAH7PS function. Acquisition of a physical gating mechanism to control catalytic function through gene fusion appears to be a general mechanism for providing allostery for this enzyme.