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Interactions of a bacterial RND transporter with a transmembrane small protein in a lipid environment

Interactions of a bacterial RND transporter with a transmembrane small protein in a lipid environment
Interactions of a bacterial RND transporter with a transmembrane small protein in a lipid environment
The small protein AcrZ in Escherichia coliinteracts with the transmembrane portion of the multidrug efflux pump AcrB and increases resistance of the bacterium to a subset of the antibiotic substrates of that transporter. It is not clear how the physical association of the two proteins selectively changes activity of the pump for defined substrates. Here, we report cryo-EM structures of AcrB and the AcrBZ complex in lipid environments, and comparisons suggest that conformational changes occur in the drug-binding pocket as a result of AcrZ binding. Simulations indicate that cardiolipin preferentially interacts with the AcrBZ complex, due to increased contact surface, and we observe that chloramphenicol sensitivity of bacteria lacking AcrZ is exacerbated when combined with cardiolipin deficiency. Taken together, the data suggest that AcrZ and lipid cooperate to allosterically modulate AcrB activity. This mode of regulation by a small protein and lipid may occur for other membrane proteins.
allostery, antibiotic, cryoEM, drug efflux, molecular dynamics, small protein, structural model, transmembrane transport
0969-2126
625-634
Du, Dijun
f7cd5fb6-5502-41e2-bc8e-ac423d350bfa
Neuberger, Arthur
7583242c-f597-41d9-86e7-9eaf1e8cac37
Wu Orr, Mona
b3f5483f-4cee-491e-9a86-b50e727aeb09
Newman, Catherine E.
88cf17e2-3fe3-4bbd-93f2-395f87832412
Hsu, Pin-Chia
4b4c8c18-752e-4ba8-a456-0fc71df1b286
Samsudin, Firdaus
b01e87a0-af50-44d6-bca4-f511c40165f9
Szewczak-Harris, Andrzej
b80501f8-248a-45bd-a7dd-9466a42dbc7f
Ramos, Leana M.
aef8af33-12ed-45db-b3dc-604763dab91b
Debela, Mekdes
ee2ef012-fb91-4d60-992c-e46a076a97a8
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Storz, Gisela
51920d35-b0b4-4c84-a4a6-b280db238003
Luisi, Ben F.
75fb3a48-d7a4-4cbf-ad81-f2ffeaaf79ff
Du, Dijun
f7cd5fb6-5502-41e2-bc8e-ac423d350bfa
Neuberger, Arthur
7583242c-f597-41d9-86e7-9eaf1e8cac37
Wu Orr, Mona
b3f5483f-4cee-491e-9a86-b50e727aeb09
Newman, Catherine E.
88cf17e2-3fe3-4bbd-93f2-395f87832412
Hsu, Pin-Chia
4b4c8c18-752e-4ba8-a456-0fc71df1b286
Samsudin, Firdaus
b01e87a0-af50-44d6-bca4-f511c40165f9
Szewczak-Harris, Andrzej
b80501f8-248a-45bd-a7dd-9466a42dbc7f
Ramos, Leana M.
aef8af33-12ed-45db-b3dc-604763dab91b
Debela, Mekdes
ee2ef012-fb91-4d60-992c-e46a076a97a8
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Storz, Gisela
51920d35-b0b4-4c84-a4a6-b280db238003
Luisi, Ben F.
75fb3a48-d7a4-4cbf-ad81-f2ffeaaf79ff

Du, Dijun, Neuberger, Arthur, Wu Orr, Mona, Newman, Catherine E., Hsu, Pin-Chia, Samsudin, Firdaus, Szewczak-Harris, Andrzej, Ramos, Leana M., Debela, Mekdes, Khalid, Syma, Storz, Gisela and Luisi, Ben F. (2020) Interactions of a bacterial RND transporter with a transmembrane small protein in a lipid environment. Structure, 28 (6), 625-634. (doi:10.1016/j.str2020.03.013).

Record type: Article

Abstract

The small protein AcrZ in Escherichia coliinteracts with the transmembrane portion of the multidrug efflux pump AcrB and increases resistance of the bacterium to a subset of the antibiotic substrates of that transporter. It is not clear how the physical association of the two proteins selectively changes activity of the pump for defined substrates. Here, we report cryo-EM structures of AcrB and the AcrBZ complex in lipid environments, and comparisons suggest that conformational changes occur in the drug-binding pocket as a result of AcrZ binding. Simulations indicate that cardiolipin preferentially interacts with the AcrBZ complex, due to increased contact surface, and we observe that chloramphenicol sensitivity of bacteria lacking AcrZ is exacerbated when combined with cardiolipin deficiency. Taken together, the data suggest that AcrZ and lipid cooperate to allosterically modulate AcrB activity. This mode of regulation by a small protein and lipid may occur for other membrane proteins.

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Accepted/In Press date: 27 March 2020
e-pub ahead of print date: 28 March 2020
Keywords: allostery, antibiotic, cryoEM, drug efflux, molecular dynamics, small protein, structural model, transmembrane transport

Identifiers

Local EPrints ID: 441826
URI: http://eprints.soton.ac.uk/id/eprint/441826
ISSN: 0969-2126
PURE UUID: e99117df-35ec-430a-9d02-a75de3cfd435
ORCID for Firdaus Samsudin: ORCID iD orcid.org/0000-0003-2766-4459
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044

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Date deposited: 29 Jun 2020 16:33
Last modified: 15 Sep 2021 02:06

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Contributors

Author: Dijun Du
Author: Arthur Neuberger
Author: Mona Wu Orr
Author: Catherine E. Newman
Author: Pin-Chia Hsu
Author: Firdaus Samsudin ORCID iD
Author: Andrzej Szewczak-Harris
Author: Leana M. Ramos
Author: Mekdes Debela
Author: Syma Khalid ORCID iD
Author: Gisela Storz
Author: Ben F. Luisi

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