洞見 - Membrane protein structure and dynamics - # Cooperative interactions between substrate-binding domains in ABC transporters

Interdomain Dynamics of the Substrate-Binding Domains in the Osmoregulatory ABC Importer OpuA

Q: How might the transient SBD-SBD interactions be regulated in response to different environmental cues or signaling pathways?

The transient interactions between substrate-binding domains (SBDs) in response to environmental cues or signaling pathways could be regulated through various mechanisms. One possible regulatory mechanism is post-translational modifications (PTMs) of the SBDs. Phosphorylation, acetylation, or ubiquitination of specific residues on the SBDs could modulate their interactions, affecting the overall transport activity of the transporter. Additionally, the binding of regulatory proteins or small molecules to the SBDs could induce conformational changes that promote or inhibit SBD-SBD interactions. Environmental cues such as changes in osmolarity, temperature, or nutrient availability could also directly impact the physical properties of the SBDs, altering their ability to interact with each other.

Q: What are the potential implications of disrupting the SBD-SBD interactions for the development of antimicrobial therapies targeting osmoregulatory transporters like OpuA?

Disrupting the SBD-SBD interactions in osmoregulatory transporters like OpuA could have significant implications for the development of antimicrobial therapies. By targeting the interactions between the SBDs, it may be possible to inhibit the transport activity of the transporter, leading to the accumulation of toxic solutes within the bacterial cell. This disruption could disrupt the osmoregulatory mechanisms of the bacteria, leading to cell death. Additionally, targeting the SBD-SBD interactions could potentially overcome antibiotic resistance mechanisms, as these interactions are essential for the efficient transport of compatible solutes. Developing small molecules or peptides that specifically interfere with SBD-SBD interactions could provide a novel approach to combating bacterial infections.

Q: Could similar cooperative interactions between substrate-binding domains be a common feature across other types of ABC transporters involved in nutrient uptake or stress response pathways?

Cooperative interactions between substrate-binding domains (SBDs) may indeed be a common feature across other types of ABC transporters involved in nutrient uptake or stress response pathways. ABC transporters often require coordinated movements of multiple domains for efficient substrate transport. In many cases, the SBDs work in concert with other domains of the transporter to facilitate substrate binding, translocation, and release. This cooperative behavior ensures the timely and accurate transport of substrates across the membrane. Therefore, it is plausible that similar cooperative interactions between SBDs exist in other ABC transporters, contributing to their overall transport efficiency and specificity. Further research into different ABC transporters could reveal the prevalence and significance of these cooperative interactions in various cellular processes.

核心概念

The substrate-binding domains (SBDs) of the osmoregulatory ABC importer OpuA transiently interact in an ionic strength-dependent manner, which is part of the transport mechanism.

摘要

The study investigates the dynamics between the two SBDs of the osmoregulatory ABC importer OpuA using single-molecule FRET (smFRET) and cryo-EM.

Key highlights:

The SBDs of OpuA exhibit two distinct FRET states - a low-FRET state representing freely diffusing SBDs and a high-FRET state indicating transient interactions between the SBDs.
The high-FRET state is responsive to changes in ionic strength and the presence of the substrate glycine betaine, suggesting direct communication between the SBDs.
Cryo-EM data corroborates the smFRET findings, showing the SBDs in closer proximity at lower ionic strengths.
The transient SBD-SBD interactions likely contribute to the cooperativity in substrate delivery observed for OpuA, enhancing the efficiency of osmoregulatory transport.
The authors propose that the physical interactions between the SBDs and the cooperativity in substrate delivery are part of the overall transport mechanism of OpuA.

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biorxiv.org

統計資料

The glycine betaine-dependent ATPase activity of OpuA-V149Q-K521C is 2-3 fold lower compared to wild-type OpuA.
The glycine betaine-dependent ATPase activities of wild-type OpuA and OpuA-V149Q-K521C are comparable when plotted relative to their maximal activities.
The dependencies of OpuA-V149Q-K521C on Mg-ATP and ionic strength (KCl concentration) are similar to wild-type OpuA.

引述

"The transient SBD-SBD interactions likely contribute to the cooperativity in substrate delivery observed for OpuA, enhancing the efficiency of osmoregulatory transport."
"The authors propose that the physical interactions between the SBDs and the cooperativity in substrate delivery are part of the overall transport mechanism of OpuA."

從以下內容提煉的關鍵洞見

The substrate-binding domains of the osmoregulatory ABC importer OpuA transiently interact

by Noort,van de... 於 www.biorxiv.org 07-13-2023

https://www.biorxiv.org/content/10.1101/2023.07.13.548808v2

深入探究

How might the transient SBD-SBD interactions be regulated in response to different environmental cues or signaling pathways?

The transient interactions between substrate-binding domains (SBDs) in response to environmental cues or signaling pathways could be regulated through various mechanisms. One possible regulatory mechanism is post-translational modifications (PTMs) of the SBDs. Phosphorylation, acetylation, or ubiquitination of specific residues on the SBDs could modulate their interactions, affecting the overall transport activity of the transporter. Additionally, the binding of regulatory proteins or small molecules to the SBDs could induce conformational changes that promote or inhibit SBD-SBD interactions. Environmental cues such as changes in osmolarity, temperature, or nutrient availability could also directly impact the physical properties of the SBDs, altering their ability to interact with each other.

What are the potential implications of disrupting the SBD-SBD interactions for the development of antimicrobial therapies targeting osmoregulatory transporters like OpuA?

Disrupting the SBD-SBD interactions in osmoregulatory transporters like OpuA could have significant implications for the development of antimicrobial therapies. By targeting the interactions between the SBDs, it may be possible to inhibit the transport activity of the transporter, leading to the accumulation of toxic solutes within the bacterial cell. This disruption could disrupt the osmoregulatory mechanisms of the bacteria, leading to cell death. Additionally, targeting the SBD-SBD interactions could potentially overcome antibiotic resistance mechanisms, as these interactions are essential for the efficient transport of compatible solutes. Developing small molecules or peptides that specifically interfere with SBD-SBD interactions could provide a novel approach to combating bacterial infections.

Could similar cooperative interactions between substrate-binding domains be a common feature across other types of ABC transporters involved in nutrient uptake or stress response pathways?

Cooperative interactions between substrate-binding domains (SBDs) may indeed be a common feature across other types of ABC transporters involved in nutrient uptake or stress response pathways. ABC transporters often require coordinated movements of multiple domains for efficient substrate transport. In many cases, the SBDs work in concert with other domains of the transporter to facilitate substrate binding, translocation, and release. This cooperative behavior ensures the timely and accurate transport of substrates across the membrane. Therefore, it is plausible that similar cooperative interactions between SBDs exist in other ABC transporters, contributing to their overall transport efficiency and specificity. Further research into different ABC transporters could reveal the prevalence and significance of these cooperative interactions in various cellular processes.