Structure of SpoT reveals evolutionary tuning of catalysis via conformational constraint

Hedvig Tamman, Karin Ernits, Mohammad Roghanian, Andres Ainelo, Christina Julius, Anthony Perrier, Ariel Talavera, Hanna Ainelo, Rémy Dugauquier, Safia Zedek, Aurelien Thureau, Javier Pérez, Gipsi Lima-Mendez, Regis Hallez, Gemma Atkinson, Vasili Hauryliuk, Abel Garcia-Pino

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Stringent factors orchestrate bacterial cell reprogramming through increasing the level of the alarmones (p)ppGpp. In Beta- and Gammaproteobacteria, SpoT hydrolyzes (p)ppGpp to counteract the synthetase activity of RelA. However, structural information about how SpoT controls the levels of (p)ppGpp is missing. Here we present the crystal structure of the hydrolase-only SpoT from Acinetobacter baumannii and uncover the mechanism of intramolecular regulation of ‘long’-stringent factors. In contrast to ribosome-associated Rel/RelA that adopt an elongated structure, SpoT assumes a compact τ-shaped structure in which the regulatory domains wrap around a Core subdomain that controls the conformational state of the enzyme. The Core is key to the specialization of long RelA-SpoT homologs toward either synthesis or hydrolysis: the short and structured Core of SpoT stabilizes the τ-state priming the hydrolase domain for (p)ppGpp hydrolysis, whereas the longer, more dynamic Core domain of RelA destabilizes the τ-state priming the monofunctional RelA for efficient (p)ppGpp synthesis. [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)334-345
Number of pages12
JournalNature Chemical Biology
Issue number3
Publication statusPublished - 5 Dec 2022


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