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Substrate inhibition imposes fitness penalty at high protein stability.

ABSTRACT: Proteins are only moderately stable. It has long been debated whether this narrow range of stabilities is solely a result of neutral drift toward lower stability or purifying selection against excess stability-for which no experimental evidence was found so far-is also at work. Here, we show that mutations outside the active site in the essential Escherichia coli enzyme adenylate kinase (Adk) result in a stability-dependent increase in substrate inhibition by AMP, thereby impairing overall enzyme activity at high stability. Such inhibition caused substantial fitness defects not only in the presence of excess substrate but also under physiological conditions. In the latter case, substrate inhibition caused differential accumulation of AMP in the stationary phase for the inhibition-prone mutants. Furthermore, we show that changes in flux through Adk could accurately describe the variation in fitness effects. Taken together, these data suggest that selection against substrate inhibition and hence excess stability may be an important factor determining stability observed for modern-day Adk.

SUBMITTER: Adkar BV

PROVIDER: S-EPMC6561296 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Substrate inhibition imposes fitness penalty at high protein stability.

Adkar Bharat V BV Bhattacharyya Sanchari S Gilson Amy I AI Zhang Wenli W Shakhnovich Eugene I EI

Proceedings of the National Academy of Sciences of the United States of America 20190516 23

Proteins are only moderately stable. It has long been debated whether this narrow range of stabilities is solely a result of neutral drift toward lower stability or purifying selection against excess stability-for which no experimental evidence was found so far-is also at work. Here, we show that mutations outside the active site in the essential <i>Escherichia coli</i> enzyme adenylate kinase (Adk) result in a stability-dependent increase in substrate inhibition by AMP, thereby impairing overal ...[more]

PMID: 31097595

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Project description:Herbicide-resistance mutations may impose a fitness penalty in herbicide-free environments. Moreover, the fitness penalty associated with herbicide resistance is not a stable parameter and can be influenced by ecological factors. Here, we used two Brachypodium hybridum accessions collected from the same planted forest, sensitive (S) and target-site resistance (TSR) to photosystem II (PSII) inhibitors, to study the effect of agro-ecological parameters on fitness penalty. Both accessions were collected in the same habitat, thus, we can assume that the genetic variance between them is relatively low. This allow us to focus on the effect of PSII TSR on plant fitness. S plants grains were significantly larger than those of the TSR plants and this was associated with a higher rate of germination. Under low radiation, the TSR plants showed a significant fitness penalty relative to S plants. S plants exhibiting dominance when both types of plants were grown together in a low-light environment. In contrast to previous documented studies, under high-light environment our TSR accession didn't show any significant difference in fitness compared to the S accession. Nitrogen deficiency had significant effect on the R compared to the S accession and was demonstrated in significant yield reduction. TSR plants also expressed a high fitness penalty, relative to the S plants, when grown in competition with wheat plants. Two evolutionary scenarios can be suggested to explain the coexistence of both TSR and S plants in the same habitat. The application of PSII inhibitors may have created selective pressure toward TSR dominancy; termination of herbicide application gave an ecological advantage to S plants, creating changes in the composition of the seed bank. Alternatively, the high radiation intensities found in the Mediterranean-like climate may reduce the fitness penalty associated with TSR. Our results may suggest that by integrating non-herbicidal approaches into weed-management programs, we can reduce the agricultural costs associated with herbicide resistance.

Dataset Information

Substrate inhibition imposes fitness penalty at high protein stability.

Publications

Substrate inhibition imposes fitness penalty at high protein stability.

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