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Human oxygen sensing may have origins in prokaryotic elongation factor Tu prolyl-hydroxylation

Scotti, JS and Leung, IKH and Ge, W and Bentley, MA and Paps, J and Kramer, HB and Lee, J and Aik, W and Choi, H and Paulsen, SM and Bowman, LAH and Loik, ND and Horita, S and Ho, CH and Kershaw, NJ and Tang, CM and Claridge, TDW and Preston, GM and McDonough, MA and Schofield, CJ (2014) 'Human oxygen sensing may have origins in prokaryotic elongation factor Tu prolyl-hydroxylation.' Proceedings of the National Academy of Sciences of the United States of America, 111 (37). 13331 - 13336. ISSN 0027-8424

2014 Scotti---Paps Human oxygen sensing may have origins in prokaryotic EF Tu PNAS.pdf

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The roles of 2-oxoglutarate (2OG)-dependent prolyl-hydroxylases in eukaryotes include collagen stabilization, hypoxia sensing, and translational regulation. The hypoxia-inducible factor (HIF) sensing system is conserved in animals, but not in other organisms. However, bioinformatics imply that 2OG-dependent prolyl-hydroxylases (PHDs) homologous to those acting as sensing components for the HIF system in animals occur in prokaryotes. We report cellular, biochemical, and crystallographic analyses revealing that Pseudomonas prolyl-hydroxylase domain containing protein (PPHD) contain a 2OG oxygenase related in structure and function to the animal PHDs. A Pseudomonas aeruginosa PPHD knockout mutant displays impaired growth in the presence of iron chelators and increased production of the virulence factor pyocyanin. We identify elongation factor Tu (EF-Tu) as a PPHD substrate, which undergoes prolyl-4-hydroxylation on its switch I loop. A crystal structure of PPHD reveals striking similarity to human PHD2 and a Chlamydomonas reinhardtii prolyl-4-hydroxylase. A crystal structure of PPHD complexed with intact EF-Tu reveals that major conformational changes occur in both PPHD and EF-Tu, including a 20-Å movement of the EF-Tu switch I loop. Comparison of the PPHD structures with those of HIF and collagen PHDs reveals conservation in substrate recognition despite diverse biological roles and origins. The observed changes will be useful in designing new types of 2OG oxygenase inhibitors based on various conformational states, rather than active site iron chelators, which make up most reported 2OG oxygenase inhibitors. Structurally informed phylogenetic analyses suggest that the role of prolylhydroxylation in human hypoxia sensing has ancient origins.

Item Type: Article
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Jordi Paps Montserrat
Date Deposited: 01 Oct 2015 09:24
Last Modified: 06 Sep 2019 10:15

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