SAMase of Bacteriophage T3 Inactivates <named-content content-type="genus-species">Escherichia coli</named-content>’s Methionine <italic toggle="yes">S</italic>-Adenosyltransferase by Forming Heteropolymers

ABSTRACT S-Adenosylmethionine lyase (SAMase) of bacteriophage T3 degrades the intracellular SAM pools of the host Escherichia coli cells, thereby inactivating a crucial metabolite involved in a plethora of cellular functions, including DNA methylation. SAMase is the first viral protein expressed upo...

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Autores principales:	Hadas Simon-Baram, Daniel Kleiner, Fannia Shmulevich, Raz Zarivach, Ran Zalk, Huayuan Tang, Feng Ding, Shimon Bershtein
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	enzyme filamentation metabolic regulation virus-host interaction cryo-EM molecular dynamics (MD) simulations bacteriophage T3 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/be476d645fd647cc9eb61ed1f2985f7c
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spelling	oai:doaj.org-article:be476d645fd647cc9eb61ed1f2985f7c2021-11-10T18:37:52ZSAMase of Bacteriophage T3 Inactivates <named-content content-type="genus-species">Escherichia coli</named-content>’s Methionine <italic toggle="yes">S</italic>-Adenosyltransferase by Forming Heteropolymers10.1128/mBio.01242-212150-7511https://doaj.org/article/be476d645fd647cc9eb61ed1f2985f7c2021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01242-21https://doaj.org/toc/2150-7511ABSTRACT S-Adenosylmethionine lyase (SAMase) of bacteriophage T3 degrades the intracellular SAM pools of the host Escherichia coli cells, thereby inactivating a crucial metabolite involved in a plethora of cellular functions, including DNA methylation. SAMase is the first viral protein expressed upon infection, and its activity prevents methylation of the T3 genome. Maintenance of the phage genome in a fully unmethylated state has a profound effect on the infection strategy. It allows T3 to shift from a lytic infection under normal growth conditions to a transient lysogenic infection under glucose starvation. Using single-particle cryoelectron microscopy (cryo-EM) and biochemical assays, we demonstrate that SAMase performs its function by not only degrading SAM but also by interacting with and efficiently inhibiting the host’s methionine S-adenosyltransferase (MAT), the enzyme that produces SAM. Specifically, SAMase triggers open-ended head-to-tail assembly of E. coli MAT into an unusual linear filamentous structure in which adjacent MAT tetramers are joined by two SAMase dimers. Molecular dynamics simulations together with normal mode analyses suggest that the entrapment of MAT tetramers within filaments leads to an allosteric inhibition of MAT activity due to a shift to low-frequency, high-amplitude active-site-deforming modes. The amplification of uncorrelated motions between active-site residues weakens MAT's substrate binding affinity, providing a possible explanation for the observed loss of function. We propose that the dual function of SAMase as an enzyme that degrades SAM and as an inhibitor of MAT activity has emerged to achieve an efficient depletion of the intracellular SAM pools. IMPORTANCE Self-assembly of enzymes into filamentous structures in response to specific metabolic cues has recently emerged as a widespread strategy of metabolic regulation. In many instances, filamentation of metabolic enzymes occurs in response to starvation and leads to functional inactivation. Here, we report that bacteriophage T3 modulates the metabolism of the host E. coli cells by recruiting a similar strategy: silencing a central metabolic enzyme by subjecting it to phage-mediated polymerization. This observation points to an intriguing possibility that virus-induced polymerization of the host metabolic enzymes is a common mechanism implemented by viruses to metabolically reprogram and subdue infected cells.Hadas Simon-BaramDaniel KleinerFannia ShmulevichRaz ZarivachRan ZalkHuayuan TangFeng DingShimon BershteinAmerican Society for Microbiologyarticleenzyme filamentationmetabolic regulationvirus-host interactioncryo-EMmolecular dynamics (MD) simulationsbacteriophage T3MicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	enzyme filamentation metabolic regulation virus-host interaction cryo-EM molecular dynamics (MD) simulations bacteriophage T3 Microbiology QR1-502
spellingShingle	enzyme filamentation metabolic regulation virus-host interaction cryo-EM molecular dynamics (MD) simulations bacteriophage T3 Microbiology QR1-502 Hadas Simon-Baram Daniel Kleiner Fannia Shmulevich Raz Zarivach Ran Zalk Huayuan Tang Feng Ding Shimon Bershtein SAMase of Bacteriophage T3 Inactivates <named-content content-type="genus-species">Escherichia coli</named-content>’s Methionine <italic toggle="yes">S</italic>-Adenosyltransferase by Forming Heteropolymers
description	ABSTRACT S-Adenosylmethionine lyase (SAMase) of bacteriophage T3 degrades the intracellular SAM pools of the host Escherichia coli cells, thereby inactivating a crucial metabolite involved in a plethora of cellular functions, including DNA methylation. SAMase is the first viral protein expressed upon infection, and its activity prevents methylation of the T3 genome. Maintenance of the phage genome in a fully unmethylated state has a profound effect on the infection strategy. It allows T3 to shift from a lytic infection under normal growth conditions to a transient lysogenic infection under glucose starvation. Using single-particle cryoelectron microscopy (cryo-EM) and biochemical assays, we demonstrate that SAMase performs its function by not only degrading SAM but also by interacting with and efficiently inhibiting the host’s methionine S-adenosyltransferase (MAT), the enzyme that produces SAM. Specifically, SAMase triggers open-ended head-to-tail assembly of E. coli MAT into an unusual linear filamentous structure in which adjacent MAT tetramers are joined by two SAMase dimers. Molecular dynamics simulations together with normal mode analyses suggest that the entrapment of MAT tetramers within filaments leads to an allosteric inhibition of MAT activity due to a shift to low-frequency, high-amplitude active-site-deforming modes. The amplification of uncorrelated motions between active-site residues weakens MAT's substrate binding affinity, providing a possible explanation for the observed loss of function. We propose that the dual function of SAMase as an enzyme that degrades SAM and as an inhibitor of MAT activity has emerged to achieve an efficient depletion of the intracellular SAM pools. IMPORTANCE Self-assembly of enzymes into filamentous structures in response to specific metabolic cues has recently emerged as a widespread strategy of metabolic regulation. In many instances, filamentation of metabolic enzymes occurs in response to starvation and leads to functional inactivation. Here, we report that bacteriophage T3 modulates the metabolism of the host E. coli cells by recruiting a similar strategy: silencing a central metabolic enzyme by subjecting it to phage-mediated polymerization. This observation points to an intriguing possibility that virus-induced polymerization of the host metabolic enzymes is a common mechanism implemented by viruses to metabolically reprogram and subdue infected cells.
format	article
author	Hadas Simon-Baram Daniel Kleiner Fannia Shmulevich Raz Zarivach Ran Zalk Huayuan Tang Feng Ding Shimon Bershtein
author_facet	Hadas Simon-Baram Daniel Kleiner Fannia Shmulevich Raz Zarivach Ran Zalk Huayuan Tang Feng Ding Shimon Bershtein
author_sort	Hadas Simon-Baram
title	SAMase of Bacteriophage T3 Inactivates <named-content content-type="genus-species">Escherichia coli</named-content>’s Methionine <italic toggle="yes">S</italic>-Adenosyltransferase by Forming Heteropolymers
title_short	SAMase of Bacteriophage T3 Inactivates <named-content content-type="genus-species">Escherichia coli</named-content>’s Methionine <italic toggle="yes">S</italic>-Adenosyltransferase by Forming Heteropolymers
title_full	SAMase of Bacteriophage T3 Inactivates <named-content content-type="genus-species">Escherichia coli</named-content>’s Methionine <italic toggle="yes">S</italic>-Adenosyltransferase by Forming Heteropolymers
title_fullStr	SAMase of Bacteriophage T3 Inactivates <named-content content-type="genus-species">Escherichia coli</named-content>’s Methionine <italic toggle="yes">S</italic>-Adenosyltransferase by Forming Heteropolymers
title_full_unstemmed	SAMase of Bacteriophage T3 Inactivates <named-content content-type="genus-species">Escherichia coli</named-content>’s Methionine <italic toggle="yes">S</italic>-Adenosyltransferase by Forming Heteropolymers
title_sort	samase of bacteriophage t3 inactivates <named-content content-type="genus-species">escherichia coli</named-content>’s methionine <italic toggle="yes">s</italic>-adenosyltransferase by forming heteropolymers
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/be476d645fd647cc9eb61ed1f2985f7c
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SAMase of Bacteriophage T3 Inactivates <named-content content-type="genus-species">Escherichia coli</named-content>’s Methionine <italic toggle="yes">S</italic>-Adenosyltransferase by Forming Heteropolymers

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