A rotary mechanism for allostery in bacterial hybrid malic enzymes

Christopher John Harding; Ian Thomas Cadby; Patrick Joseph Moynihan; Andrew Lee Lovering

doi:10.1038/s41467-021-21528-2

A rotary mechanism for allostery in bacterial hybrid malic enzymes

Christopher John Harding^*, Ian Thomas Cadby, Patrick Joseph Moynihan, Andrew Lee Lovering^*

^*Corresponding author for this work

School of Biology

Research output: Contribution to journal › Article › peer-review

Abstract

Bacterial hybrid malic enzymes (MaeB grouping, multidomain) catalyse the transformation of malate to pyruvate, and are a major contributor to cellular reducing power and carbon flux. Distinct from other malic enzyme subtypes, the hybrid enzymes are regulated by acetyl-CoA, a molecular indicator of the metabolic state of the cell. Here we solve the structure of a MaeB protein, which reveals hybrid enzymes use the appended phosphotransacetylase (PTA) domain to form a hexameric sensor that communicates acetyl-CoA occupancy to the malic enzyme active site, 60 Å away. We demonstrate that allostery is governed by a large-scale rearrangement that rotates the catalytic subunits 70° between the two states, identifying MaeB as a new model enzyme for the study of ligand-induced conformational change. Our work provides the mechanistic basis for metabolic control of hybrid malic enzymes, and identifies inhibition-insensitive variants that may find utility in synthetic biology.

Original language	English
Article number	1228
Number of pages	12
Journal	Nature Communications
Volume	12
DOIs	https://doi.org/10.1038/s41467-021-21528-2
Publication status	Published - 23 Feb 2021

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title = "A rotary mechanism for allostery in bacterial hybrid malic enzymes",

abstract = "Bacterial hybrid malic enzymes (MaeB grouping, multidomain) catalyse the transformation of malate to pyruvate, and are a major contributor to cellular reducing power and carbon flux. Distinct from other malic enzyme subtypes, the hybrid enzymes are regulated by acetyl-CoA, a molecular indicator of the metabolic state of the cell. Here we solve the structure of a MaeB protein, which reveals hybrid enzymes use the appended phosphotransacetylase (PTA) domain to form a hexameric sensor that communicates acetyl-CoA occupancy to the malic enzyme active site, 60 {\AA} away. We demonstrate that allostery is governed by a large-scale rearrangement that rotates the catalytic subunits 70° between the two states, identifying MaeB as a new model enzyme for the study of ligand-induced conformational change. Our work provides the mechanistic basis for metabolic control of hybrid malic enzymes, and identifies inhibition-insensitive variants that may find utility in synthetic biology.",

author = "Harding, {Christopher John} and Cadby, {Ian Thomas} and Moynihan, {Patrick Joseph} and Lovering, {Andrew Lee}",

note = "This project was funded by BBSRC studentship 1500753 to C.J.H. and a BBSRC David Phillips fellowship to P.J.M. (BB/S010122/1).",

year = "2021",

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doi = "10.1038/s41467-021-21528-2",

language = "English",

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journal = "Nature Communications",

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T1 - A rotary mechanism for allostery in bacterial hybrid malic enzymes

AU - Harding, Christopher John

AU - Cadby, Ian Thomas

AU - Moynihan, Patrick Joseph

AU - Lovering, Andrew Lee

N1 - This project was funded by BBSRC studentship 1500753 to C.J.H. and a BBSRC David Phillips fellowship to P.J.M. (BB/S010122/1).

PY - 2021/2/23

Y1 - 2021/2/23

N2 - Bacterial hybrid malic enzymes (MaeB grouping, multidomain) catalyse the transformation of malate to pyruvate, and are a major contributor to cellular reducing power and carbon flux. Distinct from other malic enzyme subtypes, the hybrid enzymes are regulated by acetyl-CoA, a molecular indicator of the metabolic state of the cell. Here we solve the structure of a MaeB protein, which reveals hybrid enzymes use the appended phosphotransacetylase (PTA) domain to form a hexameric sensor that communicates acetyl-CoA occupancy to the malic enzyme active site, 60 Å away. We demonstrate that allostery is governed by a large-scale rearrangement that rotates the catalytic subunits 70° between the two states, identifying MaeB as a new model enzyme for the study of ligand-induced conformational change. Our work provides the mechanistic basis for metabolic control of hybrid malic enzymes, and identifies inhibition-insensitive variants that may find utility in synthetic biology.

AB - Bacterial hybrid malic enzymes (MaeB grouping, multidomain) catalyse the transformation of malate to pyruvate, and are a major contributor to cellular reducing power and carbon flux. Distinct from other malic enzyme subtypes, the hybrid enzymes are regulated by acetyl-CoA, a molecular indicator of the metabolic state of the cell. Here we solve the structure of a MaeB protein, which reveals hybrid enzymes use the appended phosphotransacetylase (PTA) domain to form a hexameric sensor that communicates acetyl-CoA occupancy to the malic enzyme active site, 60 Å away. We demonstrate that allostery is governed by a large-scale rearrangement that rotates the catalytic subunits 70° between the two states, identifying MaeB as a new model enzyme for the study of ligand-induced conformational change. Our work provides the mechanistic basis for metabolic control of hybrid malic enzymes, and identifies inhibition-insensitive variants that may find utility in synthetic biology.

U2 - 10.1038/s41467-021-21528-2

DO - 10.1038/s41467-021-21528-2

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SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

M1 - 1228

ER -

A rotary mechanism for allostery in bacterial hybrid malic enzymes

Abstract

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