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Evolution of (p)ppGpp-HPRT regulation through diversification of an allosteric oligomeric interaction (2019)

Anderson, Brent W ; Liu, Kuanqing ; Wolak, Christine ; [et al.]

eLife Sciences Publications

In: eLife. 2019; 8: Published 2019 Sep 25. doi: 10.7554/elife.47534.

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Publication Date: 2019-09-25

Description: The alarmone (p)ppGpp regulates diverse targets, yet its target specificity and evolution remain poorly understood. Here, we elucidate the mechanism by which basal (p)ppGpp inhibits the purine salvage enzyme HPRT by sharing a conserved motif with its substrate PRPP. Intriguingly, HPRT regulation by (p)ppGpp varies across organisms and correlates with HPRT oligomeric forms. (p)ppGpp-sensitive HPRT exists as a PRPP-bound dimer or an apo- and (p)ppGpp-bound tetramer, where a dimer-dimer interface triggers allosteric structural rearrangements to enhance (p)ppGpp inhibition. Loss of this oligomeric interface results in weakened (p)ppGpp regulation. Our results reveal an evolutionary principle whereby protein oligomerization allows evolutionary change to accumulate away from a conserved binding pocket to allosterically alter specificity of ligand interaction. This principle also explains how another (p)ppGpp target GMK is variably regulated across species. Since most ligands bind near protein interfaces, we propose that this principle extends to many other protein–ligand interactions.

Electronic ISSN: 2050-084X

Topics: Biology , Medicine , Natural Sciences in General

Published by eLife Sciences Publications

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Reformulation of an extant ATPase active site to mimic ancestral GTPase activity reveals a nucleotide base requirement for function (2021)

Updegrove, Taylor B ; Harke, Jailynn ; Anantharaman, Vivek ; [et al.]

eLife Sciences Publications

In: eLife. 2021; 10: Published 2021 Mar 11. doi: 10.7554/elife.65845.

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Publication Date: 2021-03-11

Description: Hydrolysis of nucleoside triphosphates releases similar amounts of energy. However, ATP hydrolysis is typically used for energy-intensive reactions, whereas GTP hydrolysis typically functions as a switch. SpoIVA is a bacterial cytoskeletal protein that hydrolyzes ATP to polymerize irreversibly during Bacillus subtilis sporulation. SpoIVA evolved from a TRAFAC class of P-loop GTPases, but the evolutionary pressure that drove this change in nucleotide specificity is unclear. We therefore reengineered the nucleotide-binding pocket of SpoIVA to mimic its ancestral GTPase activity. SpoIVAGTPase functioned properly as a GTPase but failed to polymerize because it did not form an NDP-bound intermediate that we report is required for polymerization. Further, incubation of SpoIVAGTPase with limiting ATP did not promote efficient polymerization. This approach revealed that the nucleotide base, in addition to the energy released from hydrolysis, can be critical in specific biological functions. We also present data suggesting that increased levels of ATP relative to GTP at the end of sporulation was the evolutionary pressure that drove the change in nucleotide preference in SpoIVA.

Electronic ISSN: 2050-084X

Topics: Biology , Medicine , Natural Sciences in General

Published by eLife Sciences Publications

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Variation in the modality of a yeast signaling pathway is mediated by a single regulator (2021)

Palme, Julius ; Wang, Jue ; Springer, Michael

eLife Sciences Publications

In: eLife. 2021; 10: Published 2021 Aug 09. doi: 10.7554/elife.69974.

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Publication Date: 2021-08-09

Description: Bimodal gene expression by genetically identical cells is a pervasive feature of signaling networks, and has been suggested to allow organisms to hedge their "bets" in uncertain conditions. In the galactose-utilization (GAL) pathway of Saccharomyces cerevisiae, gene induction is unimodal or bimodal depending on natural genetic variation and pre-induction conditions. Here, we find that this variation in modality arises from regulation of two features of the pathway response: the fraction of cells that show induction, and their level of expression. GAL3, the galactose sensor, controls the fraction of induced cells, and titrating its expression is sufficient to control modality; moreover, all the observed differences in modality between different pre-induction conditions and amongst natural isolates can be explained by changes in GAL3's regulation and activity. The ability to switch modality by tuning the activity of a single protein may allow rapid adaptation of bet hedging to maximize fitness in complex environments.

Electronic ISSN: 2050-084X

Topics: Biology , Medicine , Natural Sciences in General

Published by eLife Sciences Publications

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